5ht2c Receptor antagonists in the treatment of schizophrenia

ABSTRACT

The present invention relates to the use of certain 5-HT2C receptor antagonists in the manufacture of medicaments for the treatment of mental disorders, in particular aspects of schizophrenia, cognitive impairment and suicidality, as well as to methods for determining the suitability of compounds for such a use.

The present invention relates to the use of certain compounds for thetreatment of mental disorders, in particular schizophrenia, and tomethods for determining the suitability of compounds for such a use.

BACKGROUND TO THE INVENTION

Schizophrenia, a devastating mental disorder, is a chronic diseasecharacterised by severe psychological symptoms such as perception(hallucinations), ideation, reality testing (delusions), thoughtprocesses (loose associations), feeling (flatness, inappropriateeffect), behaviour (catatonia, disorganisation), attention,concentration, motivation (avolition, impaired intentions and planning)and judgement (see for example Diagnostic and Statistical Manual ofMental Disorders IV, American Psychiatric Association). In general thedisease symptoms are divided into positive and negative symptoms withhallucinations and delusions being positive features and features suchas flatness, poverty of speech and impaired executive functionsrepresenting negative symptoms. Clinical rating scales such as Positiveand Negative Syndrome Scale (PANSS, Kay 1991) and Scale for theAssessment of Negative Symptoms (SANS, Andreasen 1982) provide criteriato differentiate between, and rate, positive and negative symptoms.Frequently included in the description of negative symptoms are thecognitive deficits schizophrenic and schizotypical patients suffer from.These include impairment in attention, verbal fluency, executivefunctions such as planning, working memory and visual and verballearning and memory. These types of cognitive dysfunction can bemeasured with a variety of tests, such as Visual Search (Portnoff et al.1981, Kurachi et al. 1994), Verbal Fluency, Wisconsin Card Sorting,Trail Making—Part B (see Goldberg et al. 1988), Symbol Digit, HopkinsVerbal Learning, Digit Span, Stroop-Color-Word and Attentional Capacity(see Mahurin et al. 1998). Importantly, it has been found that cognitivemeasures predict work function and overall outcome as assessed by theGlobal Assessment Scale and Quality of Life Scale (see Meltzer et al.1996). Several studies have now demonstrated that neuropsychologicalfunctions, reflecting several negative and cognitive symptoms of thedisease, may be more impaired in male schizophrenic patients whencompared to female patients (see Goldstein et al. 1998, 1994, Goldsteinand Link, 1988). Further, there are a number of other psychiatricdiseases such as schizotypical and schizoaffective disorder, otheracute- and chronic psychoses and bipolar disorder which have anoverlapping symptomatology with schizophrenia.

Suicide is the major cause of premature death in patients withschizophrenia, with 40% of patients reporting suicidal thoughts, 2 to40% making unsuccessful suicide attempts and 9% to 13% ending theirlives in suicide (Siris, 2001, Meltzer, 1998). Although thepathophysiology of suicide and suicidality remains unclear, the 5-HT2Areceptor has been associated with suicide (Du et al, 2001, Pandley etal, 1997). A recent report (Niswender et al, 2001) describes alteredlevels of an edited from of 5-HT2C receptor messenger RNA in suicidevictims.

The aetiology of schizophrenia is still poorly understood and the causesof the disease are thought to be multifactorial. Evidence has beengenerated to support the fact that schizophrenia is partially a geneticdisease (see Baron, 2001, Bassett et al. 2001, Tsuang et al. 2001). Thetwo most reproducible associations with schizophrenia are 1)homozygosity of a dopamine D3 receptor gene variant and 2) anon-functional polymorphism in the serotonin 5-HT2A receptor gene. It isvery likely that environmental effects also play a role in thedevelopment of the disease (Tsuang et al. 2001). Thus far, no singlegene or factor has been found to definitely associate with schizophreniaalthough many scientific findings point to a hyperactivity in theprefrontal cortex of schizophrenics and a different neuronal packing inthat brain structure. Accordingly, a reduction in the levels ofpre-synaptic gene transcripts has been found (for review see Lewis andLieberman, 2000).

Based on the pharmacological actions of antipsychotic drugs as well aspathophysiological data, several hypotheses have been suggested toexplain the aetiology of schizophrenia.

Resulting from the mechanism of action of the first generation ofanti-psychotic drugs, the dopamine hypothesis of schizophrenia wasproposed (suggesting the disease to be caused by hyperactivity of thedopaminergic system, Carlsson 1988, Seeman and Snyder 1975). As thistheory could merely explain the positive symptoms of the disease, otherhypotheses have been suggested which could explain both the positive andnegative symptomatology of schizophrenia. In particular, the glutamatehypothesis, in view of the activity of the street drug and NMDA receptorantagonist phencyclidine (PCP, angel dust), appears to clarify bothpositive and negative symptoms of the disease (see Olney et al, 1999).Nowadays, the glutamate transmitter system is considered to play aprimary role in the development, and possibly treatment, of negativesymptoms of schizophrenia (Olney et al. 1999, Bunney et al. 2000). Alsothe involvement of GABA-ergic, serotonergic and/or cholinergicneurotransmitter systems have been proposed (see Meltzer 2000, Carlssonet al. 2000, Dean 2000, Lewis et al. 1999). Further, a significant bodyof evidence points to a possible neurodevelopmental cause of the disease(see Weinberger 2000). Altogether, the origin of schizophrenia andseveral related psychiatric disorders remains unclear and it is likelythat the complex aetiology of the disease involves severalneurotransmitter systems.

Schizophrenia and related psychotic disorders are currently treated witha variety of antipsychotic drugs. However, the side-effect profile ofsuch drugs can be severe, with side effects including the frequentlydescribed extra-pyramidal syndrome (EPS) which is characterised bydyskinesia, akathasia, dystonia and Parkinsonian syndrome often of anirreversible nature (e.g. Casey et al, 1994). According to Deniker andcolleagues (Deniker, 1983) antipsychotic activity coincides with EPS andthe two could not be dissociated. This concept was generally acceptedand was confirmed when a clear correlation between dopamine D2 receptorblockade and antipsychotic activity was observed (Seeman and Lee, 1975,Creese et al, 1976) and the degree of occupancy of the same dopaminereceptor was shown to correlate with severity of EPS (Farde et al,1992).

Many neuroleptic drugs significantly reduce the positive symptoms ofschizophrenia but do not affect the negative symptoms of the disease.Further, around 25% of all schizophrenic patients aretreatment-resistant to typical antipsychotics and approximately 20% ofall patients demonstrate a very severe side-effect profile and cannot,therefore, be treated with these drugs.

Atypical antipsychotics, such as clozapine, cause little or no EPS (Matzet al, 1974, Kane et al, 1993). It has also been found that clozapine'soccupancy of the D2 receptor was lower than that of typical D2 receptorblocking antipsychotics (Farde et al. 1989, Pilowski et al. 1992).Clozapine was the first true atypical antipsychotic which significantlyimproved negative and cognitive deficits in schizophrenia. Clinicalstudies have found clozapine to be superior to typical as well as otherso-called “atypical” antipsychotic drugs—not only does it not produceEPS but also it does not induce increases in serum prolactin levels andappears to ameliorate negative symptoms of the disease.

Although nowadays many novel antipsychotics are termed “atypical”, thecriteria for this definition are not clear cut (see Meltzer et al. 1989for original criteria). Based on the activity profile of clozapine,clinical criteria for novel atypical antipsychotic drugs shouldinclude: 1) superior efficacy not only against positive but also againstnegative (including cognitive) symptoms; 2) efficacy to treat patientsrefractory to conventional antipsychotic drugs and 3) limited adverseeffects profile including no (or minimal) causation of EPS or tardivedyskinesia and a minimal effect on serum prolactin levels (seeWaddington and Quinn, 2000).

Generally, typical neuroleptic drugs are very potent dopamine D2receptor blockers. Clozapine, typifying “atypical” drugs, interacts witha large number of neurotransmitter receptors and it is thought thatinteraction with one or a few receptors may be key to its atypicalactivity. It has much lower affinity for dopamine D2 receptor andinteracts with α-adrenoceptors, histamine, serotonin (5-HT), muscarinicacetylcholine receptors in addition to certain dopamine receptors (Table1). (As the 5-HT receptor nomenclature has changed over the pastdecades, it is recommended to refer to Hoyer et al. (1994) for a recentreview.)

Table 1 represents the pharmacological characteristics (expressed asaffinity constants) of a range of typical and “atypical” antipsychoticdrugs at several human recombinant neurotransmitter receptors.

To improve the understanding of schizophrenia, genes involved in themediation of action of effective drug treatments have been studied(pharmacogenomics). For psychiatric diseases, and again specifically forschizophrenia, several receptor and “drug target” genes have beeninvestigated with respect to drug treatment response. Pickar and Rubinow(2001) review the latest data from recent pharmacogenomic studies onclozapine response in schizophrenic patients. Many of the genes encodingthe receptors with which clozapine interacts (see Table 1) have beeninvestigated for their role in clozapine treatment response.Particularly dopamine and serotonin (5-HT) receptor genes have beenstudied. Thus far no consistent associations have been found. Twostudies have reported associations between different alleles of thedopamine D3 receptor, but the results of both studies are opposing.Interestingly, several studies (six out of ten) have demonstratedpositive associations between allelic variants of the 5-HT2A receptorgene and clozapine response, although the effect is small. TABLE 1Pharmacological profiles of typical and “atypical” antipsychotic drugs*5-HT_(1A) 5-HT_(2A) 5-HT_(2C) 5-HT₃ 5-HT₆ 5-HT₇ Typical AntipsychoticChlorpromazine 5.5⁵ 8.7⁸ 7.6¹ 8.4² 7.6² Fluphenazine <5⁵   8.6⁸ 6.2¹7.8² 8.1² Fluspirilene 7.3⁶ 8.0⁶ 5.7⁶ <5.3⁶  7.5⁶ Haloperidol 5.6⁵  6.7^(6,10)  5.4¹⁰ <5.3⁶  <5.3²  6.6² 5.8⁶ 7.7⁸ 5.6¹ 6.4⁶ Loxapine 5.5⁵8.7⁸ 8.0¹ 7.8² 7.4² Pimozide 8.1⁸ <5¹   7.2² 9.3² Sulpiride <5⁸   <5¹  <5.3²  <5.3² Thioridazine 6.5⁵ 8.2⁸ 7.1¹ 7.5⁷ 7.2² 8.2² Thiothixene 5.9⁵7.3⁸ 5.8¹ 7.4² 7.9² “Atypical” Antipsychotic Amperozide  5.9¹⁹ 7.9⁸ 5.9¹<5¹⁹   7.2² 6.3² Clozapine 5.7⁵ 8.3⁸ 8.1¹  7.2¹³ 8.0⁷ 8.2² 6.9⁶ 8.0⁶7.9⁶ 7.0⁶ 8.4² 7.7⁶  8.0¹⁰ 7.7¹⁰ Fluperlapine 8.1⁸ 7.7¹ 7.8² 8.3²Iloperidone  6.8¹⁸  8.3¹⁰  7.4¹⁰  7.4¹⁰ 7.7¹⁰ Olanzapine 5.6⁶  8.8¹³ 8.2¹⁰  7.2¹³ 8.6² 7.0²  7.3¹³ 7.1⁶ 6.9⁶ Pipamperone 5.6⁶ 8.3⁶ 6.9⁶<5.3⁶  6.8⁶ Risperidone 6.4⁶ 9.7⁸  7.9¹⁰ <5.3⁶  <6⁷   8.9² 9.3⁶ 7.2⁶6.4² 8.8⁶ Seroquel 6.5⁶ 7.1⁶  5.9¹⁰ 6.8⁶ 6.5⁶ 6.8⁴ 5.4⁶ 5.4⁶ Sertindole6.6⁶ 10.0¹⁹  8.8¹⁹ 5.5⁶   9.13¹⁹ 8.0¹⁹ Ziprasidone 7.9⁶ 8.9⁶ 7.9⁶ 5.5⁶ 6.9¹⁴ 7.6¹⁴ 8.3⁶ Zotepine 6.5⁶ 9.2⁸ 8.5⁶ 6.6⁶ 9.0² 8.8² 8.6⁶ 8.0⁶ OtherDrugs Ritanserin  6.3¹¹  9.6¹¹  9.0¹¹ <5¹¹   7.8¹¹ D₁ D₂-S D₂-L D₃ D₄ D₅Typical Antipsychotic Chlorpromazine 7.3⁹  8.5¹¹ 8.3¹¹ 8.9³ 7.4¹² 9.3³8.9³  7.9⁴ Fluphenazine 7.8⁹  9.2¹⁸ 7.3¹² 8.0⁴ Fluspirilene 8.9⁶ 9.2⁶8.4⁶ 8.4⁶ Haloperidol 7.3⁹  8.7⁶ 8.7⁶ 8.1⁶ 8.3¹² 7.1¹⁰ 9.3³ 9.2³ 8.6³8.0^(4,6) Loxapine 7.5¹⁸ 8.1¹⁸ 7.9⁴ Pimozide 6.0⁹  9.7¹¹ 9.5¹¹ 9.3³7.4¹² 9.5³ 9.1³ 7.5⁴ Sulpiride <5⁹    7.0¹¹ 7.2¹¹ 8.1³ 7.3¹² 8.6³ 8.1³Thioridazine 7.9⁹  8.4¹¹ 8.1¹¹ 8.6³ 7.9¹² 8.9³ 8.6³ 8.4⁴ Thiothixene6.5⁹  9.2⁸ 7.1⁴ “Atypical” Antipsychotic Amperozide 5.1¹⁹ 6.5³ 6.4³ 6.6³Clozapine 7.4⁹  6.8⁶ 6.7⁶ 6.6⁶ 7.4⁶ 6.6¹⁰ 6.7¹⁰ 7.5³ 7.2³ 7.1³8.0^(4,12) 7.3¹⁰ Fluperlapine 6.8⁸  6.5⁸ 6.9⁴ Iloperidone 6.7¹⁰ 7.9¹⁰8.2¹⁰ 8.1¹⁰ 7.6¹⁰ 6.5¹⁰ Olanzapine 8.1¹³ 7.7⁶ 7.5⁶ 7.3⁶ 7.6^(6,13) 7.5¹⁰8.0⁴ Pipamperone 5.6⁶  7.0⁶ 6.9⁶ 6.6⁶ 8.3⁶ Risperidone 6.3¹⁰ 8.2⁶ 8.2⁶7.9⁶ 7.8⁴ 8.9³ 8.8³ 8.2³ 7.8⁶ Seroquel 5.9¹⁰ 6.4⁶ 6.2⁶ 6.5⁶ 5.8⁶ 5.9⁴Sertindole  6.89¹⁹ 8.2⁶ 7.9¹⁹ 8.0⁶ 7.6¹⁹ Ziprasidone 6.3¹⁴ 8.4⁶ 8.4¹⁴8.1¹⁴ 7.5¹⁴ 8.3⁶ 8.0⁶ 7.4⁶ Zotepine 7.5⁹  8.3⁶ 8.0⁶ 8.2⁶ 7.4⁶ 8.2⁴ OtherDrugs Ritanserin 5.9¹¹ 7.4¹¹ 7.1¹¹ M₁ M₂ M₃ M₄ M₅ mACh TypicalAntipsychotic Chlorpromazine 7.6¹⁵ 6.8¹⁵ 7.2¹⁵ 7.4¹⁵ 7.4¹⁵ 7.2¹⁶Fluphenazine 5.3¹⁶ Fluspirilene <5.3⁶   Haloperidol <5¹⁶   Loxapine7.2¹⁵ 6.5¹⁵ 6.4¹⁵ 6.5¹⁵ 6.6¹⁵ 6.3¹⁶ Pimozide Sulpiride Thioridazine8.6¹⁵ 7.9¹⁵ 7.8¹⁵ 8.0¹⁵ 7.9¹⁵ 7.7¹⁶ Thiothixene 5.6¹⁵ 5.7¹⁵ 5.8¹⁵ 5.8¹⁵5.4¹⁵ 5.5¹⁶ “Atypical” Antipsychotic Amperozide 6.3¹⁹ Clozapine 8.5¹⁵7.3¹⁵ 7.7¹⁵ 8.0¹⁵ 8.0¹⁵ 7.9¹⁶ 8.9¹³ 8.2¹³ 8.2¹³ 8.3¹³ Fluperlapine 8.1¹⁵7.1¹⁵ 7.4¹⁵ 7.9¹⁵ 7.7¹⁵ Iloperidone <5¹⁷   Olanzapine 8.6¹³ 7.9¹³ 8.0¹³8.2¹³ 8.7¹³ 7.6⁶  Pipamperone <5.3⁶   Risperidone 5.0¹⁵ 5.4¹⁵ <5¹⁵  5.5¹⁵ <5¹⁵   <5.3⁶   Seroquel 6.9¹³ 6.2¹³ 6.6¹³ 5.5¹³ 6.0⁶  Sertindole<5.6¹⁹  Ziprasidone <5.3⁶   <6¹⁴   Zotepine 7.7¹⁵ 6.9¹⁵ 7.1¹⁵ 7.1¹⁵6.6¹⁵ 6.3⁶  Other Drugs Ritanserin 5.4¹¹ α₁ α₂ H₁ sigma TypicalAntipsychotic Chlorpromazine 8.6¹⁶ 6.1¹⁶ 8.0¹⁶ Fluphenazine 8.0¹⁶ 5.8¹⁶7.7¹⁶ Fluspirilene 7.0⁶ <5.3⁶ 6.3⁶ 6.8⁶ Haloperidol 8.2¹⁶ 5.4¹⁶ 5.7¹⁶9.0⁶ Loxapine 7.6¹⁶ 5.6¹⁶ 8.3¹⁶ Pimozide Sulpiride Thioridazine 8.3¹⁶6.1¹⁶ 7.8¹⁶ Thiothixene 8.0¹⁶ 6.7¹⁶ 8.2¹⁶ “Atypical” AntipsychoticAmperozide 6.2¹⁹ 5.5¹⁹ 6.9¹⁹ 6.3¹⁹ Clozapine 8.0¹⁶ 6.8¹⁶ 8.6¹⁶ <5.3⁶Fluperlapine Iloperidone 9.6¹⁷ 7.5¹⁷ 7.5¹⁷ Olanzapine 7.2¹³ 6.6¹³ 8.2¹³<5.3⁶ Pipamperone 7.2⁶ 6.2⁶ <5.3⁶ 7.3⁶ Risperidone 8.6⁶ 8.1⁶ 7.7¹⁴ 6.0⁶8.6⁶ Seroquel 7.2⁶ 6.0⁶ 6.7⁶ <5.3⁶ Sertindole 8.7¹⁹ 6.5¹⁹ 6.3¹⁹ 6.9⁶Ziprasidone 8.0¹⁴ <6 7.3¹⁴ <5.3⁶ Zotepine 8.5⁶ 6.0⁶ 8.5⁶ 6.3⁶ OtherDrugs Ritanserin 7.5¹¹ 7.3¹¹ 8.2¹¹ 6.1¹¹*Data are expressed as affinity values (−logK_(i), or −log K_(D) ifindicated) for human receptors, if possible. See note followingreferences for species used.¹Roth et al, 1992 (rat);²Roth et al, 1994 (rat);³Malmberg et al, 1993 (human);⁴Roth et al, 1995 (rat);⁵Wander et al, 1987 (human);⁶Schotte et al, 1996 (5-HT_(1A)-rat, 5-HT_(2A)-human, 5-HT_(2C)-pig,5-HT₃-mouse, 5-HT₇-mouse, D₁-rat, D_(2/3/4)-human, mACh-rat,H₁-guinea-pig, sigma-guinea-pig);⁷Glatt et al, 1995 (rat);⁸Meltzer et al, 1989b (rat);⁹Kanba et al, 1994 (human);¹⁰Kongsamut et al, 1996 (all human with exception of rat 5-HT₆ and5-HT₇);¹¹Leysen et al. 1993a (human and for ritanserin data also rat);¹²van Tol et al, 1991 (human);¹³Bymaster et al, 1996 (human D_(1/2/4), 5-HT_(2A), 5-HT_(2C), m₁-m₅,rat 5-HT₃, α_(1/2), H₁);¹⁴Seeger et al, 1995 (all rat with exception of human D_(2/3/4) and H₁);¹⁵Bolden et al, 1992 (human, expressed as K_(D));¹⁶Richelson and Nelson, 1984 (human, expressed as K_(D));¹⁷Szewczak et al, 1995 (rat);¹⁸Corbett et al, 1993 (rat),¹⁹Leysen 2000 (human).Abbreviations used:5-HT, serotonin receptor;D, dopamine receptor;D₂-S/D₂-L, short and long form of D₂ receptor, respectively;M or mACh, muscarinic acetylcholine receptor;α, α-adrenoceptor;H, histamine receptor,sigma, σ receptor.

There are data to suggest that, of all neurotransmitter receptorstargeted by clozapine, the 5-HT2A receptor gene and possibly the D3receptor gene may play a (limited) role in the susceptibility to thedevelopment of schizophrenia and maybe also participate in the responseto clozapine treatment.

Other serotonin receptor targets, such as the 5-HT2C receptor (gene),have not been highlighted in these reviews and are believed not to playa significant role in either risk to the disease or response toclozapine treatment (see O'Donovan and Owen, 1999, Baron, 2001, Bassettet al. 2001, Pickar and Rubinow, 2001). Substantial research efforts arecurrently underway to identify genes or factors which represent a moresignificant risk factor to schizophrenia and/or related psychiatricdisorders.

Although it has been recognised that clozapine and several othereffective (atypical) antipsychotics are potent 5-HT2C receptorantagonists, a possible role for 5-HT2C receptor antagonism inantipsychotic medication is generally not favoured. For example, Cantonand colleagues (1991) presented data suggesting a correlation between5-HT2C receptor affinity and efficacy of clozapine (and atypicalantipsychotic activity in general). However, Roth and co-workers (1992)presented data demonstrating that high affinity for the 5-HT2C receptordoes not correlate with their selection of “atypical” antipsychotics andtherefore discarded the hypothesis that 5-HT2C receptor antagonism maybe an important component of atypical antipsychotic drugs. Furtherreviews, which have discussed the putative role of 5-HT2C receptorantagonists in antipsychotic treatments, have primarily concluded that5-HT2C receptor antagonism 1) does not contribute to antipsychoticactivity (Leysen et al. 1993), 2) leads to weight gain (Leysen 2000) and3) that it functionally opposes 5-HT2A receptor antagonism (Meltzer1999).

Although several of the new generation of antipsychotic drugsdemonstrate limited extra-pyramidal side effects (often only at lowdoses), not all are devoid of increases of prolactin release (asspecified in the original definition). Further, few of the newantipsychotics have been reported to ameliorate negative symptoms orcognitive deficits of the disease.

U.S. Pat. No. 6,335,371 describes a method for inducing cognitionenhancement in a mammal by administration of deramciclane andderivatives thereof, these compounds being 5HT2A and/or 5HT2C receptorantagonists.

Several groups including, Altar et al. (1986), Leysen and colleagues(1988, 1993) and Meltzer (1994, 1996, 1999), recognized that manyeffective antipsychotic drugs have a high 5-HT2A receptor affinity inaddition to moderate to high affinity for the D2 receptor. Meltzer etal. reported that specifically “atypical” antipsychotics have a highratio of 5-HT2A/D2 receptor affinity (Meltzer et al. 1989, reporting ratdata). However, the correlation between the 5-HT2A/D2 ratio was notideal, e.g. loxapine and zotepine were outliers, and it was suggestedthat it should only be used as a rapid screening tool. Table 2 lists the5-HT2A/D2 receptor affinity ratios for typical and “atypical”antipsychotics determined mainly at human recombinant receptors and asimilar relationship as reported by Meltzer et al. (1989) can beobserved. TABLE 2 Receptor Affinity ratios for several typical andatypical antipsychotic drugs* 5-HT_(2C)/ 5-HT_(2C)/ 5- 5-HT_(2A) D2(2C/2A) + HT_(2A)/D₂ (2C/2A) (2C/D2) (2C/D2) H₁/D₂ Typical AntipsychoticChlorpromazine 1.01 0.87 0.88 1.75 0.93 Fluphenazine 0.93 0.72 0.67 1.390.84 Fluspirilene 0.87 0.71 0.62 1.33 0.68 Haloperidol 0.75 0.76 0.611.37 0.63 Loxapine 1.07 0.92 0.99 1.91 1.02 Pimozide 0.87 <0.6 <0.54<1.14 Sulpiride <0.65 <1 <0.65 <1.65 Thioridazine 0.98 0.87 0.85 1.720.93 Thiothixene 0.79 0.79 0.63 1.43 0.89 “Atypical” AntipsychoticAmperozide 1.23 0.76 0.92 1.67 1.08 Clozapine 1.16 0.98 1.14 2.12 1.23Fluperlapine 1.25 0.95 1.18 2.13 Iloperidone 1.01 0.89 0.90 1.79Olanzapine 1.17 0.89 1.04 1.93 1.05 ORG-5222 1.10 1.02 1.13 2.15 1.02Pipamperone 1.20 0.83 1.0 1.83 <0.77 Risperidone 1.12 0.80 0.89 1.69 0.9Seroquel 1.13 0.81 0.92 1.73 1.08 Sertindole 1.27 0.89 1.11 1.99 0.79Ziprasidone 1.06 0.89 0.94 1.83 0.87 Zotepine 1.08 0.96 1.06 2.02 1.06Other Drugs Ritanserin 1.29 0.94 1.22 2.15 1.10*For the affinity ratios, data from Table 1 have been used During thepast decade, the relatively high affinity of atypical antipsychoticdrugs for the 5-HT2A receptor combined with lower affinity for D2receptors has generally been seen as the single most important factordifferentiating atypical from typical antipsychotic drugs (Richelson1996, Leysen et# al. 1993, Meltzer 1994, 1996, 1999). Other pharmacologicalcharacteristics thought to be of importance in “atypical” antipsychoticactivity are dopamine D1 and/or D4 receptor antagonism, possiblyserotonin 5-HT1A, 5-HT6 and 5-HT7 receptor antagonism, anticholinergicproperties and adrenergic α1-receptor antagonism (Lieberman, 1993,Meltzer, 1994, 1999, Richelson, 1996, Leysen, 2000).

In spite of the extensive studies that have been performed in respect ofthe treatment of schizophrenia, particularly in the assessment of therelationship between the desirable effects caused by atypicalanti-psychotics and receptor antagonism, there remains a need for theidentification of candidate drugs which address cognitive deficits, aswell as the negative aspects of the condition in particular, but whichalso address the aspects of the condition which result in suicide.

SUMMARY OF THE INVENTION

The present invention is based upon the discovery that compounds whichantagonise the 5-HT2C receptor are particularly suitable for thetreatment of certain groups of schizophrenia sufferers, as well as forthe treatment of patients suffering from related disorders. Theinvention also provides means for determining the suitability ofcompounds for use in the treatment of schizophrenia and relatedpsychiatric disorders. More particularly, the relative affinity ofcandidate compounds for the 5-HT2C receptor is assessed and, dependenton that affinity, the suitability of such compounds for the treatment ofschizophrenia and related psychiatric disorders is determined.

DETAILED DESCRIPTION OF THE INVENTION

In its first aspect, the present invention provides the use of a 5-HT2Creceptor antagonist in the manufacture of a medicament for the treatmentof cognitive dysfunction in and/or negative symptoms of schizophrenia,in the treatment of refractory schizophrenia or in the treatment ofsuicidality or mild cognitive impairment, with the proviso that:

(a) for the indications cognitive dysfunction, negative symptoms ofschizophrenia and refractory schizophrenia, the 5-HT2C receptorantagonist is other than ritanserin, clozapine, fluperlapine, loxapine,ORG-5222, pipamperone, sertindole, olanzapine, zotepine or ziprasidone;

(b) for the indications cognitive dysfunction in schizophrenia or mildcognitive impairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and

(c) for the treatment of schizophrenic suicidality, the 5-HT2C receptorantagonist is other than clozapine.

In its second aspect, the present invention provides the use of acompound having a relative 5-HT2C affinity of ≧1.80, wherein therelative 5-HT2C affinity is determined according to formula I:${Formula}\quad{I:{\frac{X}{A} + \frac{X}{B}}}$[wherein X is the average affinity of a compound for interaction at the5-HT2C receptor and A and B are the average affinity values of acompound for interaction at two major sites other than the 5-HT2Creceptor] in the preparation of a medicament for the treatment ofcognitive dysfunction in and/or negative symptoms of schizophrenia, inthe treatment of refractory schizophrenia or in the treatment ofsuicidality or mild cognitive impairment, with the proviso that:(a) for the indications cognitive dysfunction, negative symptoms ofschizophrenia or refractory schizophrenia, the compound is other thanritanserin, clozapine, fluperlapine, loxapine, ORG-5222, pipamperone,sertindole, olanzapine, zotepine or ziprasidone;(b) for the indications cognitive dysfunction in schizophrenia or mildcognitive impairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and(c) for the treatment of schizophrenic suicidality, the compound isother than clozapine.

In a third aspect, the present invention provides a method fordetermining the suitability of a candidate compound for use in thetreatment of cognitive dysfunction in and/or negative symptoms ofschizophrenia, refractory schizophrenia, suicidality or mild cognitiveimpairment, which comprises:

-   -   a) assessing the affinity of the compound at the 5-HT2C        receptor;    -   b) assessing the affinity of the compound at at least two other        major sites of said compound interaction;    -   c) applying the assessed affinities to the following formula:        ${\frac{X}{A} + \frac{X}{B}} = Y$        [wherein: X is the average affinity of a compound for        interaction at the 5-HT2C receptor and A and B are the average        affinity values of a compound for interaction at two major sites        other than the 5-HT2C receptor]; and selecting compounds in        which Y≧1.80 as suitable compounds for the treatment of        cognitive dysfunction in and/or negative symptoms of        schizophrenia, refractory schizophrenia, suicidality or mild        cognitive impairment, provided that:        (a) for the treatment of cognitive dysfunction in or negative        symptoms of schizophrenia or refractory schizophrenia, the        compound selected is other than ritanserin, clozapine,        fluperlapine, loxapine, ORG-5222, pipamperone, sertindole,        olanzapine, zotepine or ziprasidone;        (b) for the indications cognitive dysfunction in schizophrenia        or mild cognitive impairment, the 5-HT2C receptor antagonist is        other than        (1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,        (1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane        and pharmaceutically acceptable acid addition salts thereof; and        (c) for the treatment of schizophrenic suicidality, the compound        selected is other than clozapine.

In a preferred embodiment of this aspect of the invention, there isprovided a method for determining the suitability of a candidatecompound for use in the treatment of cognitive dysfunction in and/ornegative symptoms of schizophrenia or refractory schizophrenia, whichcomprises:

-   -   a) assessing the affinity of the compound at the 5-HT2C        receptor;    -   b) assessing the affinity of the compound at at least two other        major sites of said compound interaction;    -   c) applying the assessed affinities to the following formula:        ${\frac{X}{A} + \frac{X}{B}} = Y$        [wherein: X is the affinity of a compound for interaction at the        5-HT2C receptor and A and B are the average affinity values of a        compound for interaction at two major sites other than the        5-HT2C receptor];        (d) and selecting compounds in which Y≧1.80 as suitable        compounds for the treatment of cognitive dysfunction in and/or        negative symptoms of schizophrenia or refractory schizophrenia,        provided (i) that the compound selected is other than        ritanserin, clozapine, fluperlapine, loxapine, ORG-5222,        pipamperone, sertindole, olanzapine, zotepine or ziprasidone;        and (ii) when the compound selected is for use in the treatment        of cognitive dysfunction, the compound is other than        (1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,        (1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane        and pharmaceutically acceptable acid addition salts thereof.

In a further preferred embodiment of this aspect of the invention, thereis provided a method for determining the suitability of a candidatecompound for use in the treatment of suicidality or mild cognitiveimpairment, which comprises:

-   -   a) assessing the affinity of the compound at the 5-HT2C        receptor;    -   b) assessing the affinity of the compound at at least two other        major sites of said compound interaction;    -   c) applying the assessed affinities to the following formula:        ${\frac{X}{A} + \frac{X}{B}} = Y$        [wherein: X is the affinity of a compound for interaction at the        5-HT2C receptor and A and B are the average affinity values of a        compound for interaction at two major sites other than the        5-HT2C receptor];        (e) and selecting compounds in which Y≧1.80 as suitable        compounds for the treatment of suicidality or mild cognitive        impairment, with the proviso that, (i) for the treatment of        schizophrenic suicidality, the compound selected is other than        clozapine; and (ii) for the treatment of mild cognitive        impairment, the compound is other than        (1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,        (1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane        and pharmaceutically acceptable acid addition salts thereof.

In another aspect, the present invention provides a method for thetreatment of a patient suffering from symptoms associated with acondition selected from the group consisting of negative symptoms ofschizophrenia, cognitive dysfunction, refractory schizophrenia,suicidality and mild cognitive impairment with a pharmaceuticallyeffective amount of a 5-HT2C antagonist, with the proviso that:

(a) when the condition is selected from the group consisting of negativesymptoms of schizophrenia, cognitive dysfunction and refractoryschizophrenia, the 5-HT2C receptor antagonist is other than ritanserin,clozapine, fluperlapine, loxapine, ORG-5222, pipamperone, sertindole,olanzapine, zotepine or ziprasidone;

(b) when the condition is cognitive dysfunction in schizophrenia or ismild cognitive impairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and

(c) when the condition is schizophrenic suicidality, the 5-HT2C receptorantagonist is other than clozapine.

In a yet further aspect, the present invention provides a method for thetreatment of a patient suffering from symptoms associated with acondition selected from the group consisting of negative symptoms ofschizophrenia, cognitive dysfunction, refractory schizophrenia,suicidality and mild cognitive impairment with a pharmaceuticallyeffective amount of a compound having a relative 5-HT2C affinity of≧1.80, wherein the relative 5-HT2C affinity is determined according toformula I: ${Formula}\quad{I:{\frac{X}{A} + \frac{X}{B}}}$[wherein X is the average affinity of a compound for interaction at the5-HT2C receptor and A and B are the average affinity values of acompound for interaction at two major sites other than the 5-HT2Creceptor] with the proviso that:(a) when the condition is selected from the group consisting ofcognitive dysfunction, negative symptoms of schizophrenia or refractoryschizophrenia, the compound is other than ritanserin, clozapine,fluperlapine, loxapine, ORG-5222, pipamperone, sertindole, olanzapine,zotepine or ziprasidone;(b) for the indications cognitive dysfunction in schizophrenia and mildcognitive impairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and(c) when the condition is schizophrenic suicidality, the compound isother than clozapine.

In the present invention, A and B are different and can, independently,be any site which binds the compound, including receptors, channels,enzymes or any other protein, such as any of the receptors listed inTable 1.

In a preferred embodiment of these aspects of the invention, A and B aredifferent and are independently selected from the group consisting ofthe 5-HT1A, 5-HT2A, 5-HT₃, 5-HT₆, 5-HT₇, D₁, D₂-S, D₂-L, D₃, D₄, D₅ M₁,M₂, M₃, M₄, M₅, mACh, α1, α2, H₁ or sigma receptors.

More preferably A and B are different and are independently selectedfrom the group consisting of the 5-HT₃, 5-HT₄, 5-HT₆, 5-HT₇, D₁, D₂, D₃,M₁, M₂, M₃, M₄, M₅, α₁, α₂ or H₁ receptors.

In a most preferred embodiment of these aspects of the invention, A istypically a measurement of the affinity of the compound for the 5-HT2Areceptor.

In a further most preferred embodiment of these aspects of theinvention, B is typically a measurement of the affinity of the compoundfor the D2 receptor.

In a more preferred embodiment of these aspects of the invention, A is ameasurement of the affinity of the compound for the 5-HT2A receptor andB is a measurement of the affinity of the compound for the D2 receptor.

Affinity of a compound for any of the receptors, channels, enzymes orproteins such as those listed in Table 1 can be measured usingtechniques common in the art. Typically, affinity is measured as logKi(pKi) or logKd (pKd).

In the present invention, compounds having a value for Y in Formula Igreater than or equal to 1.80 are deemed as being particularly suitablefor use in the treatment of the specific patient groups of theinvention. It is generally the case that the higher the value for Y, themore suitable is the compound for use in the treatment of the specificpatient groups detailed herein. In a preferred embodiment of the presentinvention, Y is equal to or greater than 2.00, although it is mostpreferred that Y is equal to or greater than 1.90.

5-HT2C receptor antagonists and, in particular such compounds having arelative 5-HT2C affinity ≧1.80 are useful in the treatment of cognitivedysfunction in and/or negative symptoms of schizophrenia, refractoryschizophrenia, suicidality or mild cognitive impairment.

Compounds such as ritanserin, clozapine, fluperlapine, loxapine,ORG-5222, pipamperone, sertindole, olanzapine, zotepine or ziprasidoneare already known for the treatment of schizophrenia and are henceexcluded for the purposes of the present invention for use in themanufacture of a medicament for the treatment of cognitive dysfunctionin or negative symptoms of schizophrenia or refractory schizophrenia.Clozapine is also known for the treatment of suicidality inschizophrenic patients and is hence excluded therefrom for the purposesof this invention. As discussed above, U.S. Pat. No. 6,335,371 disclosesthe use of deramciclane, N-desmethylderamciclane and pharmaceuticallyacceptable acid addition salts thereof in the treatment of cognitivedysfunction in, i.a., psychiatric disorders and hence the presentapplication excludes this use for these compounds.

Cognitive dysfunction is typified by impairment in attention, verbalfluency, executive functions such as planning, working memory and visualand verbal learning and memory. In some patients with schizophrenia,cognitive functioning declines with impaired attention, abstractthinking and problem solving. Severity of cognitive impairment is amajor determinant of overall disability in these patients.

In accordance with the present invention, it has been discovered that5-HT2C receptor antagonists are useful in the treatment of thesesymptoms and the present invention therefore provides the use of a5-HT2C receptor antagonist in the manufacture of a medicament for thetreatment of cognitive dysfunction in a schizophrenic patient, with theproviso that the 5-HT2C receptor antagonist is other than ritanserin,clozapine, fluperlapine, loxapine, ORG-5222, pipamperone, sertindole,olanzapine, deramciclane, N-desmethylderamciclane, zotepine orziprasidone.

Negative (deficit) symptoms of schizophrenia include blunted affect,poverty of speech, anhedonia and asociality. With blunted affect(flattening of emotions), the patient's face may appear immobile, withpoor eye contact and lack of expressiveness. Poverty of speech refers toa dimunition of thought reflected in decreased speech and terse repliesto questions, creating the impression of inner emptiness. Anhedonia(diminished capacity to experience pleasure) may be reflected by a lackof interest in activities with substantial time being spent inpurposeless activity. Asociality refers to a lack of interest inrelationships. Negative symptoms are often associated with a generalloss of motivation and diminished sense of purpose and goals. Patientswith a “deficit subtype” of schizophrenia have prominent negativesymptoms unaccounted for by other factors. Such patients are typicallymore disabled, have a poorer prognosis and are more resistant totreatment than those with a “nondeficit subtype” of schizophrenia.

In accordance with the present invention it has been discovered that5-HT2C receptor antagonists are useful in the treatment of negativesymptoms of schizophrenia, and the present invention therefore providesthe use of a 5-HT2C receptor antagonist in the manufacture of amedicament for the treatment of negative symptoms of schizophrenia, withthe proviso that the 5-HT2C receptor antagonist is other thanritanserin, clozapine, fluperlapine, loxapine, ORG-5222, pipamperone,sertindole, olanzapine, zotepine or ziprasidone.

Negative symptoms of schizophrenia can be found either together with orin isolation from cognitive dysfunction in schizophrenic patients.Excluded from the present invention is the use of(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof in themanufacture of a medicament for the treatment of cognitive dysfunctionin a patient also suffering from negative symptoms of schizophrenia.

Refractory schizophrenia is a term given to embrace those schizophrenicpatients who do not respond to conventional antipsychotic drugs. Thisgroups generally makes up approximately 30% of all schizophrenicpatients. In accordance with the present invention, it has beendiscovered that 5-HT2C receptor antagonists are useful in the treatmentof refractory schizophrenia and the present invention therefore providesthe use of a 5-HT2C receptor antagonist in the manufacture of amedicament for the treatment of refractory schizophrenia, with theproviso that the 5-HT2C receptor antagonist is other than ritanserin,clozapine, fluperlapine, loxapine, ORG-5222, pipamperone, sertindole,olanzapine, zotepine or ziprasidone.

Suiciality may or may not be associated with schizophrenia. Suicidalityis often associated with people with personality disorders, particularlyemotionally immature people who have a borderline or an antisocialpersonality disorder, tolerate frustration poorly and react to stressimpetuously with violence and aggression.

According to the Merck Manual of Diagnosis and Therapy, 17^(th) Edition(www.merck.com/pubs/mmanual), suicidal behaviour includes suicidegestures, attempted suicide and completed suicide. Suicide plans andactions that appear unlikely to succeed are often termed “suicidegestures”; they are predominantly communicative and are generally pleasfor help. It is important to aim treatment at relieving misery andpreventing repeated attempts, particularly as 20% of people who attemptsuicide try again within 1 year and 10% finally succeed. “Attemptedsuicide” is a suicidal act that is not fatal, possibly because theself-destructive intention was slight, vague or ambiguous or the actiontaken had a low lethal potential. Most people who attempt suicide areambivalent about their wish to die and the attempt may be a plea forhelp and may fail because of a strong wish to live. “Completed suicide”results in death.

Some patients with schizophrenia attempt suicide and may or may not besuccessful. In chronic schizophrenia, suicide may result from theepisodes of depression to which these patients are prone. The suicidemethod is usually bizarre and often violent. Attempted suicide isuncommon, although it may be the first gross sign of psychiatricdisturbance, occurring early in schizophrenia, possibly when the patientbecomes aware of the disorganisation of his thought and volitionalprocesses.

In accordance with the present invention, there is provided the use of a5-HT2C receptor antagonist in the manufacture of a medicament for thetreatment of suicidality, with the proviso that, when the suicidality isin a schizophrenic patient, the 5-HT2C receptor antagonist is other thanclozapine. Suicidality may be in a schizophrenic or non-schizophrenicpatient and, in a preferred aspect, therefore, the present inventionprovides the above use of a 5-HT2C receptor antagonist wherein thesuicidality is in a schizophrenic patient, with the proviso that the5-HT2C receptor antagonist is other than clozapine. In an alternativelypreferred aspect, the present invention provides the above use of a5-HT2C receptor antagonist wherein the suicidality is not in aschizophrenic patient.

Mild cognitive impairment is a term given to patients whose clinicalstate presents as memory impaired, but who are otherwise functioningwell and do not meet the clinical criteria for dementia. Mild cognitiveimpairment represents a transitional state of cognitive impairmentbetween normal aging and early Alzheimer disease. Diagnostic criteriatypically include memory complaint (preferably corroborated), objectivememory impairment, normal general cognitive function, intact activitiesof daily living but no dementia. Mild cognitive impairment may also bereferred to as incipient dementia, questionable dementia, age-associatedcognitive decline and isolated memory impairment and the presentinvention embraces all these, and other commonly used, synonyms for mildcognitive impairment. Numerous studies have been performed on mildcognitive impairment and the reviews of these studies have indicatedthat individuals with mild cognitive impairment are at an increased riskof developing Alzheimer disease and, in most cases, convert to dementiaand/or Alzheimer disease within several years.

In accordance with the present invention, there is provided the use of a5-HT2C receptor antagonist in the manufacture of a medicament for thetreatment of mild cognitive impairment, with the proviso that the 5-HT2Creceptor antagonist is other than deramciclane orN-desmethylderamciclane or pharmaceutically acceptable acid additionsalts thereof.

Compounds appropriate for use in the indications above will typically be5-HT2C receptor antagonists. Receptor affinity may be known forindividual compounds from the art, or may be determined either using themethods described herein or by alternative methods known from the art.

Any compound demonstrating 5-HT2C receptor antagonist activity may beused in the present invention. Suitable compounds include thosedescribed in the following patent publications: WO 97/16429, WO97/44334, U.S. Pat. No. 5,010,078, EP 161,218, EP 401,707, EP 526,434,DE 02834114, EP 210,893, U.S. Pat. No. 3,580,916, U.S. Pat. No.5,043,341, EP 620,222, EP 208,235, EP 437,790, DE 02614406, U.S. Pat.No. 4,338,317, EP 271,013, EP 110,435, EP 398,326, WO 92/05170, WO95/01976, WO 96/23783, WO 98/04289, WO 97/48700, WO 00/48602, WO00/26186, WO 99/58490, WO 99/52517, WO 99/51237, WO 99/46245, WO99/43319, WO 99/33841, WO 99/33840, WO 99/25356, WO 99/09017, WO99/03833, WO 99/00119, WO 98/56367, WO 98/52943, WO 98/50358, WO98/50346, WO 98/50343, WO 98/41527, WO 98/38165, WO 98/30561, WO98/30546, WO 98/24785, WO 98/21958, WO 98/04261, WO 97/48699, WO97/41858, WO 97/39001, WO 97/37989, WO 97/20845, WO 97/12880, WO97/08167, WO 97/06155, WO 97/00872, WO 96/39382, WO 96/30366, WO96/24351, WO 96/23769, WO 96/18629, WO 96/14320, WO 96/11930, WO96/11929, WO 96/02537, WO 95/29177, WO 95/25731, WO 95/24194, WO95/21844, WO 95/18117, WO 95/12591, WO9 94/22871, WO 94/18958, WO94/18182, WO 94/18170, WO 94/14801, WO 94/04533, WO 94/02462, WO93/18028, WO 93/18026, WO 93/16081, WO 93/16051, WO 93/14758, WO93/12790, WO 92/15302, WO 92/10192, WO 91/18602, WO 01/68585, WO01/68067, WO 01/52855, WO 01/38329, WO 01/26621, WO 01/25229, WO01/19371, WO 00/76984, WO 00/68181, WO 00/63185, WO 00/62782, WO00/61129, WO 00/61128, WO 00/37068, WO 00/06165, U.S. Pat. No.6,143,325, U.S. Pat. No. 5,854,248, U.S. Pat. No. 5,739,336, U.S. Pat.No. 5,693,645, U.S. Pat. No. 5,674,875, U.S. Pat. No. 5,498,618, U.S.Pat. No. 5,371,093, U.S. Pat. No. 5,266,571, U.S. Pat. No. 5,116,852,U.S. Pat. No. 5,106,855, U.S. Pat. No. 5,030,656, U.S. Pat. No.5,013,735, U.S. Pat. No. 4,985,352, U.S. Pat. No. 4,914,107, U.S. Pat.No. 4,914,100, U.S. Pat. No. 4,906,639, U.S. Pat. No. 4,902,691, U.S.Pat. No. 4,891,376, U.S. Pat. No. 4,847,261, JP 13220375, JP 12204040,JP 11171865, JP 11080155, JP 10316634, JP 10077271, JP 09040646, JP08053416, JP 08040999, JP 07228573, JP 07179337, JO 00158067, GB02303303, GB 02301774, EP 01118610, EP 1070716, EP 01052245, EP01000944, EP 00905136, EP 00797995, EP 00797994, EP 00769297, EP00749971, EP 00749967, EP 00718299, EP 00700905, EP 00686393, EP00682015, EP 0661266, EP 00657426, EP 006554440, EP 00613898, EP00596449, EP 00559569, EP 00545120, EP 00522226, EP 00511074, EP00511073, EP 00493687, EP 00484988, EP 00465398, EP 00452074, EP00389352, EP 00388081, EP 00384228, EP 00379308, EP 00378468, EP00375297, EP 00374042, EP 00373998, EP 00363963, EP 00354030, EP00337136, EP 00332528, EP 00320983, EP 00218433 and EP 00145494.

The present invention thus includes the use of a compound as describedin any of the above patent applications in the manufacture of amedicament for the treatment of cognitive dysfunction in or negativesymptoms of schizophrenia, refractory schizophrenia, suicidality or mildcognitive impairment.

In addition to the compounds described in the above applications, thefollowing compounds are suitable for use in the present invention:AHR-16303B (AH Robins Co. Inc), AP-792 and AT-1015 (Ajinomoto Co. Inc.),BMS-181102 (Bristol Myers Squibb), CV-5197 (Takeda Chemical IndustriesLtd), dotarizine (Ferrer Internacional SA), E-2101 (Eisai Co Ltd),eltoprazine (Solvay SA), emopamil (Knoll AG), HT-90B (ChugaiPharmaceutical Co Ltd), ICI-169369 and ICI-170809 (Zeneca Group plc),LU-26042 and LU-29066 (H Lundbeck A/S), NPC-18166 (Scios Inc), Org-38457(NV Organon), pelanserin (Cinvestav), perbufylline (Siegfried Group),SB-206553 and SB-242084 (SmithKline Beecham), SR-46615A (SanofiRecherche SA), SUN-9221 (Suntory Ltd) tropoxin (Russian Academy MedicalScience) and YM-992 (Yamanouchi Pharmaceutical Co Ltd).

The present invention thus also provides the use of any of AHR-16303B(AH Robins Co. Inc), AP-792 and AT-1015 (Ajinomoto Co. Inc.), BMS-181102(Bristol Myers Squibb), CV-5197 (Takeda Chemical Industries Ltd),dotarizine (Ferrer Internacional SA), E-2101 (Eisai Co Ltd), eltoprazine(Solvay SA), emopamil (Knoll AG), HT-90B (Chugai Pharmaceutical Co Ltd),ICI-169369 and ICI-170809 (Zeneca Group plc), LU-26042 and LU-29066 (HLundbeck A/S), NPC-18166 (Scios Inc), Org-38457 (NV Organon), pelanserin(Cinvestav), perbufylline (Siegfried Group), SB-206553 and SB-242084(SmithKline Beecham), SR-46615A (Sanofi Recherche SA), SUN-9221 (SuntoryLtd) tropoxin (Russian Academy Medical Science) and YM-992 (YamanouchiPharmaceutical Co Ltd) in the manufacture of a medicament for use in thetreatment of cognitive dysfunction in or negative symptoms ofschizophrenia, refractory schizophrenia, suicidality or mild cognitiveimpairment.

Particularly preferred 5-HT2C receptor antagonists for the uses of thepresent invention include Ro-60-0759, RS-102221, SDZ-SER-082,Amersergide, ICI-169369, Sergolexole, Deramciclane,N-desmethyl-deramciclane, CGS-18102A and LU-26042. These compounds,together with methods for their preparation are described in WO98/30546, U.S. Pat. No. 5,739,336, EP 473,550, U.S. Pat. No. 4,931,447,U.S. Pat. No. 4,435,405, U.S. Pat. No. 4,714,704, U.S. Pat. No.4,342,762, U.S. Pat. No. 6,093,747, EP 161,218 and WO 93/14758respectively.

Examples of candidate compounds for which the relative 5-HT2C affinityhas been calculated according to formula I, above, from known5-HT2C/5-HT2A/D2 affinities include those listed in Table 3, below, inwhich known anti-psychotic drugs are shown in bold typeface. TABLE 3Formula I 5-HT2C 5-HT2A D2 Affinity Compound Affinity Affinity AffinityRatio Patent Number CAS Number Ro-60-0759 8.5 6.1 6 2.81 WO-09830546RS-102221 8.2 5.8 6 2.78 US-05739336 185376-97-0 SDZ-SER-082 7.8 6 62.60 EP-0473550 141474-54-6 Amesergide 8.2 7.8 6 2.42 US-04931447ICI-169369 8 7.7 6.5 2.27 US-04435405 85273-96-7 Sergolexole 7.2 7.2 62.20 US-04714704 N-Desmethyl- 7.2 7 7 2.20 US06093747 deramciclaneRitanserin 9 9.6 7.4 2.15 Clozapine 8 8.2 7 2.12 Deramciclane 7.8 8 72.09 US-04342762 120444-71-5 CGS-18102A 7.2 6.6 7.4 2.06 EP-00161218LU-26042 7.8 8.8 6.9 2.02 WO-09312790/ WO-09314758 Sertindole 8.8 101.99 Olanzapine 7.8 8.8 1.93 Ziprasidone 7.9 8.9 1.83* Affinities expressed as pKi or pKd values

As is evident from this table, the relative 5-HT2C affinity is above1.80 for each of the compounds listed and each of these compounds(excluding ritanserin, clozapine, sertindole, olanzapine andziprasidone) is therefore suitable for the use of the present invention.In addition, ritanserin, sertindole, olanzapine and ziprasidone aresuitable for use in the treatment of suicidality or mild cognitiveimpairment and clozapine is suitable for use in the treatment of mildcognitive impairment and suicidality in a non-schizophrenic patient.

In a further aspect, therefore, the present invention provides one ofRo-60-0759, RS-102221, SDZ-SER-082, Amesergide, ICI-169369, Sergolexole,CGS-18102A and LU-26042 for use in the manufacture of a medicament forthe treatment of cognitive dysfunction in and/or negative symptoms ofschizophrenia, refractory schizophrenia, suicidality or mild cognitiveimpairment.

In an alternative embodiment of this aspect of the invention, there isprovided the use of deramiclcane, N-desmethyl-deramciclane or apharmaceutically acceptable acid addition salt thereof in themanufacture of a medicament for the treatment of negative symptoms ofschizophrenia (when not associated with cognitive dysfunction),refractory schizophrenia or suicidality.

Most preferred in this aspect of the invention is one of Amesergide,Sergolexole, CGS-18102A or LU-26042 for use in the manufacture of amedicament for the treatment of cognitive dysfunction in and/or negativesymptoms of schizophrenia, refractory schizophrenia, suicidality or mildcognitive impairment; or deramiclcane, N-desmethylderamciclane or apharmaceutically acceptable acid addition salt thereof in themanufacture of a medicament for the treatment of negative symptoms ofschizophrenia (when not associated with cognitive dysfunction),refractory schizophrenia or suicidality.

1. Deramciclane

Deramciclane is(1R,2S,4R)-(−)-2-[2-(N,N-dimethylamino)-ethoxy]-2-phenyl-1,7,7-trimethylbicyclo[2.2.1]heptaneand is described in U.S. Pat. No. 4,342,762.

Deramciclane has the structural formula shown above. In man,deramciclane undergoes biotransformation into N-desmethyl-deramciclane,which is an active metabolite with even more pronounced 5-HT2C receptorantagonism (U.S. Pat. No. 6,093,747).

2. Amesergide

Amesergide is N-cyclohexyl-1-isopropyl-6-methyl-ergoline-8-carboxamideand has the following structural formula:

The compound is described in U.S. Pat. No. 4,931,447 and is known toblock 5HT2A/2C mediated elevations of prolactin levels induced byD-fenfluramine. The metabolism of amesergide has been evaluated inrhesus monkeys, with maximum values of parent compounds or metabolites(4-hydroxy and desisopropyl species) usually occurring on day 35, withminimum values occurring on day 365, suggesting that elimination ortransformation of amesergide was enhanced as the study progressed.

3. Sergolexole

Sergolexole (chemical name:[trans(8β)]6-methyl-1-[1-methylethyl]ergoline-8-carboxylic acid,4-methoxycyclohexyl ester (maleate salt)) and its preparation, isdescribed in U.S. Pat. No. 4,714,704. The compound, having thestructural formula shown below, is known to be useful in the treatmentof migraine.

4. CGS-18102A

This compound(10-methoxy-4-propyl-1,2,3,4a,5,10b-hexahydro-4H-[1]-benzopyrano[3,4-b]pyridinehydrochloride) is described in EP 161,218 and has the followingstructural formula:

This compound is a potent 5HT2A/2C receptor antagonist that has beenproposed for use as an anxiolytic or antidepressant drug.

5. LU-26042

This compound1-{2-[4[(2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl)-1-piperidinyl]ethyl}-2-imidazolidinone,is a known 5-HT2A/2C receptor antagonist, described in WO 93/12970 andWO 93/14758. The compound has the following structural formula:

In addition to the above, the present invention also provides a productcontaining a 5-HT2C receptor antagonist and a typical antipsychotic as acombined preparation for simultaneous, separate or sequential use inschizophrenia therapy. In a preparation suitable for this use, the5-HT2C receptor antagonist is as described herein. The typicalantipsychotic would generally be a compound suitable for the generaltreatment of schizophrenia, and preferably suitable for thosesub-classes of schizophrenia not treatable by a 5-HT2C receptorantagonist, for example the positive symptoms. An example of such acompound includes haloperidol, chlorpromazine, fluphenazine,fluspirilene, loxapine, pimozide, sulpiride, thioridazine andthiothixene. The combination of the two compounds would therefore resultin the treatment of all or substantially all schizophrenic symptoms.

Analysis of “Atypical” Antipsychotics

With the recent introduction of several “atypical” antipsychotic drugsto the market, a large amount of information on clinical efficacy andside effects of these drugs has become available. Although few of theserecently introduced drugs have been compared in clinical trials side byside, recent published reports provide much greater insight intopossible relationships between clinical effects and pharmacologicalproperties of the drugs. Thus, the clinical characteristics of the drugsclozapine, olanzapine, risperidone, seroquel (quetiapine), sertindoleand ziprasidone were compared and rated based on recent literaturereports (Meltzer 2000, Javitt 2001, Azorin et al. 2001, Sauriol et al.2001, Conley and Mahmoud 2001, Chakos et al. 2001, Cuesta et al. 2001,Wetterling 2001, Taylor and McAskill 2000, Purdon et al. 2000, Leucht etal. 1999, Pezawas et al. 2000, Lewis et al. 2000, Meltzer and McGurk1999, Arvanitis and Miller, 1997 and Tran et al. 1997).

The different clinical read-outs have been grouped: 1) extra-pyramidalside effects (includes causation of tardive dyskinesia) 2) improvementof negative symptoms (includes effects on flatness, social withdrawaland anhedonia) 3) improvement of cognitive dysfunction 4) increases inserum prolactin levels 5) increase in weight gain. These effects, inaddition to suppressing positive symptoms of the disease, representfeatures desirable for candidate compounds.

Tables 4 and 4A show an overview of clinical characteristics (A) andcertain receptor affinity ratios (B) of currently marketed andclinically well evaluated “atypical” antipsychotic drugs* TABLE 4AExtra- Improve- Improve- “Atypical” pyramidal ment ment Increases Anti-side negative cognitive prolactin Weight psychotic effects symptomsdeficits** levels Gain Clozapine 3 1 1-2 3 1 Risperidone 1 3 2-3 1 2-3Olanzapine 1-2 2 1-2 2 2 Sertindole 3 2 3 2-3 Seroquel 2 3 2-3 3 2Ziprasidone 2 2 3 3*grading: 1-high, 2-medium and 3-low probability.References used: (Meltzer 2000, Javitt 2001, Azorin et al. 2001, Sauriolet al. 2001, Conley and Mahmoud 2001, Chakos et al. 2001, Cuesta et al.2001, Wetterling 2001, Taylor and McAskill 2000, Leucht et al. 1999,Pezawas et al. 2000, Lewis et al. 2000, Arvanitis and Miller, 1997 andTran et al. 1997)**for ratings of specific cognitive measures see Table 3.

TABLE 4B 5-HT2C/ “Atypical” 5-HT2A 5-HT2C/ Anti- 5-HT2A/ ratio D2 ratio(2C/2A) + H1/D2 psychotic D2 ratio (2C/2A) (2C/D2) (2C/D2) ratioClozapine 1.22 0.98 1.14 2.12 1.23 Risperidone 1.09 0.79 0.90 1.69 0.9Olanzapine 1.13 0.88 1.04 1.92 1.05 Sertindole 1.25 0.89 1.02 1.91 0.71Seroquel 1.15 0.81 0.92 1.73 1.08 Ziprasidone 1.06 0.89 0.94 1.83 0.87

The clinical characteristics of antipsychotic drugs can be correlatedwith their pharmacological properties.

1. Extra Pyramidal Side Effects (EPS)

Although the induction of EPS has been an important part of“atypicality” as defined by Meltzer et al. (1989), the current analysisis the first to demonstrate that there is a correlation between thelevel of induction of EPS and the 5-HT2A/D2 receptor affinity ratio(FIG. 1, Panel A). As many 5-HT2A receptor antagonists also interactwith 5-HT2C receptors, it was investigated whether an associationexisted between EPS and relative 5-HT2C receptor affinity (expressed asthe sum of the 5-HT2C/5-HT2A and 5-HT2C/D2 affinity ratios in formula Iabove). FIG. 1 (Panel C) demonstrates the absence of a robustrelationship. Further possible correlations between receptor affinityratios and the level of EPS induction were assessed and as shown in FIG.1 (Panels E, G, I, K, M, O, Q). Although the correlation between EPSliability and 5-HT2A/D2 ratio is not perfect (ziprasidone appears to bean outlier) it is possible that over time, when head to head comparativetrials have been done and drugs have been prescribed more widely, thecorrelation will improve.

In summary it is suggested that blockade of the 5-HT2A receptor is animportant factor in the suppression (or prevention) of D2receptor-induced EPS.

2. Improvement of Negative Symptoms

Thus far, there is no (new) antipsychotic which appears to havecomparable efficacy to clozapine in treating negative symptoms.Similarly, clozapine is the most effective drug to treatneuroleptic-refractory patients. The present analysis demonstrates thatof all pharmacological properties possessed by the novel antipsychoticagents, the relative 5-HT2C receptor affinity (expressed as the sum of5-HT2C/5-HT2A and 5-HT2C/D2 affinity ratios in the formula above) wasmost discernibly correlated with improvement of negative symptoms (seeFIG. 1, Panel B). Similarly, the 5-HT2C/5-HT2A and 5-HT2C/D2 affinityratios separately demonstrated clear correlations with efficacy to treatnegative symptoms (FIG. 1, Panels F and H).

Thus, although it is not suggested that the absolute 5-HT2C receptoraffinity (see Table 1) correlates with this clinical effect (aspreviously investigated by Roth et al. 1992), it is suggested that therelative 5-HT2C receptor affinity (when compared to both 5-HT2A and D2receptor affinities) shows a clear relationship with therapeuticefficacy in the treatment of negative symptoms. Comparisons of otherpharmacological properties of the antipsychotic drugs did not reveal thesame degree of correlation (FIG. 1, Panels D, J, L, N, P and R). Forexample, a correlation between 5-HT2A/D2 affinity ratio and improvementof negative symptoms was absent (FIG. 1, Panel D).

In summary, it is suggested that blockade of the 5-HT2C receptor isimportant in treating cognitive dysfunction in or the negative symptomsof schizophrenia, refractory schizophrenia, suicidality or mildcognitive impairment.

FIG. 2. Correlation Plots of Clinical Read-Outs for AtypicalAntipsychotic Drugs and Neurotransmitter Receptor Affinity Ratios (SeeTable 4a and b for data)

3. Improvement of Cognitive Deficits

There is limited information on the effects of novel antipsychotic drugson cognitive deficits of schizophrenic patients. It is evident, however,that conventional neuroleptic drugs do not improve cognitive dysfunctionin schizophrenia. Reportedly, clozapine has significant effects onseveral cognitive functions as determined by a range ofneuropsychological tests (Hagger et al. 1993, Green et al. 1997).Similarly, preliminary studies have demonstrated improvement tocognitive function by olanzapine and to a lesser extent by risperidoneand quetiapine (Meltzer 2000b-chapter int, Meltzer and McGurk 1999,Cuesta et al. 2001, Purdon et al. 2000, Velligan et al. 2002, Purdon etal. 2001, Meltzer 2000). Table 5 represents the different levels ofeffect of the drugs as reported in these literature sources. TABLE 5Effects of “Atypical” Antipsychotic Drugs on Various Cognitive FunctionsCognitive Effect Clozapine Olanzapine Risperidone Quetiapine Attention++ − + + Executive Function + + + + Verbal Learning +/− ++ − − VerbalMemory + ++ − + Working Memory +/− − ++ − Verbal Fluency ++ ++ − +

Although the trials have been sparse, it appears that clozapine andolanzapine may be more effective in improving cognitive deficits inschizophrenia than risperidone or quetiapine. As clinical data on onlyfour novel antipsychotics was available, correlations between receptoraffinity and clinical effect are weak (see FIG. 2). However, whencompared to other correlations, it seems that the association withrelative 5-HT2C receptor affinity is most relevant (Panel A). Although,the relationship with 5-HT2A or 5-HT6 cannot be excluded (Panels B andD), the 5-HT2C receptor affinity appears to be a contributing factorwhen compared to the 5-HT2A affinity of the drugs (Panel C).

4. Increases in Serum Prolactin Levels

As has been reported previously, there does not seem to be a clearcorrelation between pharmacological characteristics and the level ofserum prolactin increase of antopsychotic agents. As pictured in FIG. 2(Panel A) a rather unclear trend may be observed of relative affinity tothe D2 receptor. We do not wish to speculate however on the possiblepharmacological properties involved in the response.

5. Weight Gain

Increase in weight gain, varying from 0.8-3.5 kg per month, has beenreported for a number of novel antipsychotic agents. Haloperidol incontrast does not have such an effect. Clozapine, olanzapine andseroquel reportedly do cause weight gain (Taylor and McAskill, 2000,Wetterling 2001). As demonstrated in FIG. 2 (Panel B) a relationshipbetween H1/D2 receptor affinity and increasing liability for weight gainexists. This is not a novel finding and has been previously reported(Wirshing et al. 1999).

To conclude, rather than evaluating the “atypicality” of antipsychoticdrugs the present results demonstrate that different pharmacologicalproperties of antipsychotic agents may be responsible for differentfeatures of atypicality of these drugs. There is likely to be asignificant grey area whereby antipsychotics possess certain atypicalcharacteristics but not all.

Importantly, new correlations between the 5-HT2A/D2 receptor affinityratio and causation of EPS but more importantly between relative 5-HT2Creceptor affinity and the improvement of negative symptoms, cognitivedeficits, refractory schizophrenia, suicidality or mild cognitiveimpairment have been revealed. This finding will be of great value inthe development of drugs that are effective in the treatment of patientssuffering from these symptoms.

5-HT2C Receptor Antagonism and Suicide

As mentioned above Niswender and colleagues (2001) have reportedincreased levels of 5-HT2C messenger RNA editing. It remains unclear,however, what role the 5-HT2C receptor would play and whether agonistsor antagonists to the 5-HT2C receptor could have beneficial effects onsuicidal behaviour. Further analysis of the data published by Niswenderet al. (2001) demonstrates that there may be differences between maleand female patients, their drug treatments, levels of 5-HT2C receptormRNA editing and possibly suicide rate (see Table 6). TABLE 6 Levels of5-HT2C receptor mRNA editing (A form) in depressive, schizophrenic andcontrol subjects (with and without suicide) Control Major Depression*Schizophrenia* Females 82.8 83.4 77.6 83.2 86.6 78.6 84.2 87.8 79   90.3

87.8 89   Average 83.4 87.0 82.1 SEM 0.51  1.65  2.23 Males 77.3 77.873.6 79.9 80.8 82.7 82.2 80.8 84.4 82.9 84.3

83.1 84.8 85.9 84.5 84.8 86.2 84.7 87.3 86.6 85.1 87.5 85.5 88.6 90.5Average 83.6 84.1 83.5 SEM 1.17  1.28  1.85*in bold: subject comitted suicide/in italics subject's latest drugtreatment blocked 5-HT2C receptors

A strong trend for women with major depression to have 40 increasedlevels of the Edit-A form of 5-HT2C receptor mRNA was observed (p=0.04,Student's t-test, p=0.09, ANOVA). Also, the data were re-analysedconsidering the type of drug treatment the donor received (the latestbefore death). The types of drug treatment were classified as 1) drugsknown to antagonise the 5-HT2C receptor (such as clozapine, loxapine orolanzapine) and 2) other drugs (e.g. haloperidol) or no drug treatmentat all. Then, a trend for a correlation between level of Edit-A 5-HT2Creceptor mRNA and 5-HT2C receptor blocking drug treatments was revealed(see Table 7). Further, although the sample set was small, a possiblerelationship between treatment with 5-HT2C receptor blocking drugs and alower suicide rate was observed. TABLE 7 Comparison of Edit-A 5-HT2Creceptor mRNA levels in schizophrenic patients with and without drugtreatment* blocking 5-HT2C receptors Schizophrenia Drug treatment withDrug treatment without 5-HT2C antagonism 5-HT2C antagonism 78.6 77.680.7 79 73.6 87.8 82.7 89 84.4 85.9 84.8 86.2 86.6 Average 80.8 84.6 SEM1.89 1.81 p (t-test) = 0.07 p (ANOVA) = 0.14*The subject's latest drug treatment included blockade of 5-HT2Creceptors

Thus, of seven schizophrenic patients not treated with drugs blockingthe 5-HT2C receptor, four committed suicide, whereas of the six patientspreviously treated with 5-HT2C receptor blocking antipsychotic drugs,only two committed suicide. Larger studies will be needed to confirm thepresent observations. Nevertheless, it may be possible that the 5 HT2Cblocking effects of antipsychotic drugs reduce suicide completion ratesin schizophrenic, and perhaps other, psychiatric patients.

Thus, to conclude, the present study is the first to reveal a distinctrole for 5-HT2C receptor antagonists in the treatment of the negativesymptoms or cognitive deficits of schizophrenia or refractoryschizophrenia.

Further, 5-HT2C receptor antagonists may be of benefit in the treatmentof suicidality or mild cognitive impairment.

While it is possible for the 5-HT2C receptor antagonist to beadministered alone, it is preferable to present the compound as apharmaceutical composition (e.g. formulation) comprising at least oneactive compound together with one or more pharmaceutically acceptablecarriers, adjuvants, excipients, diluents, fillers, buffers,stabilisers, preservatives, lubricants, or other materials well known tothose skilled in the art and optionally other therapeutic orprophylactic agents.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

Suitable carriers, excipients, etc. can be found in standardpharmaceutical texts, for example, Remington's Pharmaceutical Sciences,18th edition, Mack Publishing Company, Easton, Pa., 1990.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Suchmethods include the step of bringing into association the activecompound with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association the active compound with liquidcarriers or finely divided solid carriers or both, and then if necessaryshaping the product.

Formulations may be in the form of liquids, solutions, suspensions,emulsions, elixirs, syrups, tablets, lozenges, granules, powders,capsules, cachets, pills, ampoules, ointments, gels, pastes, creams,sprays, mists, foams, lotions, oils, suppositories, boluses or sustainedrelease formulations.

Formulations suitable for oral administration (e.g. by ingestion) may bepresented as discrete units such as capsules, cachets or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or suspension in an aqueous or non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion; as a bolus; as an electuary; or as a paste.

A tablet may be made by conventional means, e.g., compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine the activecompound in a free-flowing form such as a powder or granules, optionallymixed with one or more binders (e.g. povidone, gelatin, acacia,sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers ordiluents (e.g. lactose, microcrystalline cellulose, calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc, silica);disintegrants (e.g. sodium starch glycolate, cross-linked povidone,cross-linked sodium carboxymethyl cellulose); surface-active ordispersing or wetting agents (e.g. sodium lauryl sulfate); andpreservatives (e.g. methyl p-hydroxybenzoate, propyl p-hydroxybenzoate,sorbic acid). Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activecompound therein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile. Tablets mayoptionally be provided with an enteric coating, to provide release inparts of the gut other than the stomach.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol or the like. Inaddition, if desired, the pharmaceutical compositions to be administeredmay also contain minor amounts of non-toxic auxiliary substances such aswetting or emulsifying agents, pH buffering agents and the like, such asfor example, sodium acetate, sorbitan monolaurate, triethanolamineoleate, triethanolamine sodium acetate, etc.

A more recently devised approach for parenteral administration employsthe implantation of a slow-release or sustained-release system, suchthat a constant level of dosage is maintained. See, e.g., U.S. Pat. No.3,710,795.

The percentage of active compound contained in such parentalcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject. However,percentages of active ingredient of 0.1% to 10% in solution areemployable, and will be higher if the composition is a solid which willbe subsequently diluted to the above percentages. Preferably, thecomposition will comprise 0.2-2% of the active agent in solution.

Depot formulations, such as those comprising a microsphere-baseddelivery system wherein the active compound is incorporated into amatrix of poly-(DL-lactide-co-glycolide) (PLG), may otherwise be used.In such instances, release profiles can be adjusted by manipulation offormulation parameters and through control of the fabrication process.

Formulations suitable for topical administration may comprise a patch ora dressing such as a bandage or adhesive plaster impregnated with activecompounds and optionally one or more excipients or diluents.

It will be appreciated that appropriate dosages of the active compounds,and compositions comprising the active compounds, can vary from patientto patient. Determining the optimal dosage will generally involve thebalancing of the level of therapeutic benefit against any risk ordeleterious side effects of the treatments of the present invention. Theselected dosage level will depend on a variety of factors including, butnot limited to, the activity of the particular compound, the route ofadministration, the time of administration, the rate of excretion of thecompound, the duration of the treatment, other drugs, compounds, and/ormaterials used in combination, and the age, sex, weight, condition,general health, and prior medical history of the patient. The amount ofcompound and route of administration will ultimately be at thediscretion of the physician, although generally the dosage will be toachieve local concentrations at the site of action which achieve thedesired effect without causing substantial harmful or deleteriousside-effects.

Administration in vivo can be effected in one dose, continuously orintermittently (e.g. in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician.

In general, a suitable dose of a 5-HT2C receptor antagonist will besimilar to that described during the original preparation and use of thecompound. This may be in the form of a single bolus dose or morepreferably in multiple applications or a sustained release preparation.Factors such as age, weight, sex and presence or absence of otherdiseases, may have a bearing on the suitable daily dose.

When the 5-HT2C receptor antagonist is deramciclane orN-desmethyl-deramciclane, an oral daily dose of between 10 mg and 60 mgwill be appropriate, preferably of about 30 mg.

When the 5-HT2C receptor antagonist is Amesergide, an oral daily dose ofbetween 50 mg and 150 mg will be appropriate, preferably of about 100mg.

When the 5-HT2C receptor antagonist is Sergolexole, an oral daily doseof between 10 mg and 150 mg will be appropriate, preferably of about 50mg.

The present invention furthermore provides a product, for example a kit,containing a 5HT2C receptor antagonist together with a typicalantipsychotic as a combined preparation for simultaneous, separate orsequential use in schizophrenia or suicidality therapy or the treatmentof cognitive impairment.

In this aspect of the invention, the 5HT2C receptor antagonist issubstantially as herinabove defined, or may be identified by use of amethod substantially as hereinabove defined. Typical antipsychotics areknown and available. The choice of antipsychotic will depend on variousfactors such as, for example, the nature and severity of the conditionto be treated, as well as the particular 5HT2C receptor antagonist alsoforming a part of the product.

The precise format for performing methods of the invention may be variedby those of skill in the art using routine skill and knowledge.

Of course, the person skilled in the art will design any appropriatecontrol experiments with which to compare results obtained in methods ofthe invention.

All documents mentioned in this specification are hereby incorporated byreference.

EXAMPLES

This exemplification details the determination of affinity values(affinity values expressed as Ki or Kd or antagonist activity as IC50,Kb or A2- or the -log of any of these values) of compounds at eitherrecombinant receptors expressed stably in a cell line (example 1) ortransiently (example. 2). Furthermore references are given for thedetermination of such values in tissue homogenates from rat, mouse,human and porcine brain using a variety of methods.

Example 1 Method Taken from Berg et al. 1999

Cell Culture. Chinese hamster ovary K1 (CHO-K1) cell lines that stablyexpress human 5-HT2C receptors at '250 fmol/mg (“low” expressing,CHO-1C19) and 5 to 10 pmol/mg (“high” expressing, CHO-1C7) were used inthis study. Cells were maintained in a minimal essential mediumsupplemented with 5% fetal bovine serum and 300 mg/ml hygromycin. Forall experiments, cells were seeded into 12- or 24-well tissue culturevessels at a density of 4 3 10 4 cells/cm². After a 24-h plating period,cells were washed with Hanks' balanced salt solution (HBSS) and placedinto Dulbecco's modified Eagle's medium/F-12 [1:1] with 5 mg/ml insulin,5 mg/ml transferrin, 30 nM selenium, 20 nM progesterone, and 100 mMputrescine (serum free media) and grown for an additional 24 h beforeexperimentation. The absence of receptor reserve for 5-HT on botheffector pathways (PLC and PLA2) coupled to the human 5-HT2C receptor inCHO-1C19 cells (Berg et al., 1998) has been previously demonstrated.

IP Accumulation and AA Release Measurements.

IP accumulation and AA release were measured as described previously(Berg et al., 1994a, 1996, 1998). Unless stated otherwise, measurementsof PLC-mediated IP accumulation were made from the same multiwell(simultaneously) as PLA2-AA release measurements (Berg et al., 1998).Briefly, cells in serum-free medium were labeled with 1 mCi/ml[3H]-myoinositol (25 Ci/mmol) for 24 h and with 0.1 mCi/ml [3H]AA (220Ci/mmol) for 4 h at 37° C. After the labeling period, cells were washedthree times with HBSS containing calcium and magnesium, 20 mM HEPES, and0.1% fatty acid-free bovine serumalbumin (BSA; experimental medium).Between washes, the cells were incubated for 5 min in a 37° C. waterbath (15-min total wash and preincubation time). After the washprocedure, cells were incubated in 0.5 ml of experimental mediumcontaining vehicle (H20 or 0.01% DMSO) or the indicated drugconcentrations. For measurement of basal effector activity, cells wereincubated at 37° C. for 25 min. For measurement of agonist-mediatedstimulation of effector activity, cells were incubated at 37° C. for 10min. After incubation, aliquots (100 ml) of cell media were addeddirectly to scintillation vials for measurement of [3H] content (Berg etal., 1996, 1998). The remaining media were aspirated quickly and 1 ml 10mM formic acid (4° C.) was added to extract the accumulated [3H]-IPs(IP1, IP2, and IP3, collectively referred to as IP; Berg et al., 1994a).For some experiments, data were normalized to protein content, which wasmeasured according to the method of Lowry et al. (1951).

Receptor Binding Studies.

5-HT2C receptor saturation binding experiments were done as describedpreviously (Berg et al., 1994a). Briefly, cells were washed twice withHBSS, scraped, and centrifuged at 500 g for 5 min. Cell pellets wereflash frozen in liquid nitrogen and stored at 2135° C. until use. Allmembrane preparation procedures were done at 4° C. Cell pellets werethawed, resuspended in 20 volumes of homogenization buffer (50 mM HEPES,2.5 mM MgCl₂, 2.0 mM EGTA pH 7.4 at 22° C.), homogenized twice with apolytron (setting no. 7) for 15s (separated by 15s), and centrifuged(39,000 g; 4° C.; 10 min). The resulting membrane pellet was washedthree times with homogenization buffer and resuspended in assay buffer(homogenization buffer containing 0.1% ascorbic acid) for use in thebinding assay. Aliquots (250 ml) of membrane suspension (50 mg protein)were incubated (60 min; 37° C.; total volume 5 500 ml) with 13concentrations (0.01-40 nM) of [3H]-mesulergine. Nonspecific binding wasdetermined in the presence of 1 mM mianserin. Samples were filteredthrough polyethyleneimine-coated Whatman GF/C filters (Whatman Inc.,Clifton, N.J.) with a Brandel Cell Harvester (Brandel Laboratories,Gaithersburg, Md.). The filters were washed twice with 1.5 ml ice-coldbuffer and counted with a Beckman LS7500 liquid scintillation counter(Beckman Instruments, Berkeley, Calif.). Protein was determined with themethod of Lowry et al. (1951) using BSA as a standard.

Data Analysis

Concentration response data were fit with non-linear regression to themodel: $\begin{matrix}{E = \frac{E_{\max}}{1 + \left\lbrack \frac{{EC}_{50}}{A} \right\rbrack^{n}}} & (1)\end{matrix}$where E is the measured response at a given agonist concentration (A),E_(max)=maximal response, EC₅₀=the concentration of agonist producinghalf-maximal response, and n=slope index. Calculation of apparentantagonist dissociation constants (K_(B)) was determined with theequation: $\begin{matrix}{K_{B} = \frac{\lbrack B\rbrack}{{dr} - 1}} & (2)\end{matrix}$where B is the concentration of the antagonist used and dr representsthe ratio (dose ratio) of concentrations (EC₅₀) that produced equivalentresponses in the absence and presence of antagonist. Data fromsaturation binding studies were analyzed with nonlinear regressionanalysis. After fitting nonspecific data to the equation describing astraight line with the origin at 0,0 (y=mx) to determine m, totalbinding data were fit to equation 3 to provide estimates of B_(max),K_(d), and slope factor (n): $\begin{matrix}{B = {\frac{B_{\max}}{\left\lbrack {\frac{K_{d}}{\lbrack A\rbrack} + 1} \right\rbrack^{n}} + {m\lbrack A\rbrack}}} & (3)\end{matrix}$where m is the slope of the linear regression line for nonspecificbinding.

Example 2 Method Taken from Herrick-Davis et al. 2000

Cell Culture and Transfection

COS-7 cells were grown in Dulbecco's modified Eagle's medium (DMEM) with10% fetal bovine serum in a humidified incubator with 5% CO₂ at 37° C.Twenty-four hours before transfection, cells were seeded at 10⁵cells/well in 24-well cluster plates for IP assays and for[³H]mesulergine binding studies performed in parallel to monitorreceptor expression. Cells were transfected with the rat or human 5-HT2Creceptor by combining 2 ml of lipofectAMINE with 0.5 mg of plasmid DNAin 400 ml of serum-free DMEM and added to each well for 5 h at 37° C./5%CO₂. For radioligand binding studies, COS-7 cells were seeded at 80%confluence in 100-mm dishes and transfected with 5 mg of plasmid DNA, 20ml of lipofectamine in 4 ml of serum-free DMEM for 5 h at 37° C./5% CO₂.After transfection, cells were returned to complete culture medium for48 h before membrane preparation for radioligand binding studies.

IP Production Assays

IP production was measured according to the method of Herrick-Davis etal., 1999. In brief, 24 h after transfection COS-7 cells were washedwith PBS and labeled over-night with 0.5 mCi/well of myo-[³H]inositol ininositol-free/serum-free DMEM at 37° C./5% CO₂. After labeling, cellswere washed with PBS and preincubated in inositol-free/serum-free DMEMwith 10 mM LiCl and 10 mM pargyline (assay medium) for 10 min.Antipsychotic drugs were added during the 10-min preincubation. 5-HT, orassay medium alone, was added to each well and incubation continued foran additional 35 min to determine basal activity. Assay medium wasremoved and cells were lysed in 200 ml of stop solution (1 M KOH/18 mMsodium borate/3.8 mM EDTA) and neutralized by adding 200 ml of 7.5% HCl.The contents of each well were extracted with 3 volumes ofchloroform:methanol (1:2, v/v) and centrifuged 5 min at 10,000 g, andthe upper layer was loaded onto a 1-ml AG1-X8 resin (100-200 mesh)column. Columns were washed with 10 ml of 5 mM myo-inositol and 10 ml of5 mM sodium borate/60 mM sodium formate. Total [³H]IPs were eluted with3 ml of 0.1 M formic acid/1 M ammonium formate. Radioactivity wasmeasured by liquid scintillation counting in Ecoscint cocktail.

Radioligand Binding

Membranes were prepared by scraping a confluent 100-mm dish oftransfected COS-7 cells into 20 ml of 50 mM Tris-HCl/5 mM MgSO₄/0.5 mMEDTA, pH 7.4 (assay buffer) and centrifugation at 10,000 g for 30 min.Membranes were resuspended in 20 ml of assay buffer, homogenized, andcentrifuged again. After resuspension in 15 ml of assay buffer, 0.5-mlmembrane aliquots were added to each assay tube containing 1 nM[³H]mesulergine and varying concentrations of competing drug in a finalvolume of 1 ml. Mianserin (10 mM) was used to define nonspecificbinding. Samples were incubated at 37° C. for 30 min, filtered throughglass fiber filters (presoaked in 0.3% polyethylenamine) on a Brandelcell harvester, and counted in Ecoscint cocktail in a liquidscintillation counter (Beckman, Berkeley, Calif.) at 40% efficiency.

Data Analyses. Data analyses were performed using Prism software(GraphPad, San Diego, Calif.). The Cheng/Prusoff equation was used tocalculate Ki values from IC50 values.

Further examples are as detailed in the method sections of the followingreferences:

The binding of serotonergic ligands to the porcine choroids plexus:characterization of a new type of serotonin recognition site” Pazos A,Hoyer D and J M Palacios, Eur J. Pharmacol. 1985, 106:539-546

Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat andpig brain membranes: radioligand binding studies with [3H)5-HT,(3H]8-OH-DPAT, (−)[¹²⁵I]iodocyanopindolol, [3H]mesulergine and[3H]ketanserin” Hoyer D, Engel G and HO Kalkman, Eur J. Pharmacol. 1985,118(1-2):13-23

“Quantitative autoradiographic mapping of serotonin receptors in the ratbrain. I. Serotonin-1 receptors” Pazos A and J M Palacios, Brain Res.1985; 346(2):205-30

“Serotonin 5-HT1C receptors are expressed at high density on choroidplexus tumors from transgenic mice” Yagaloff K A, Lozano G, Van Dyke T,Levine A and P R Hartig, Brain Res. 1986, 385(2):389-94

“[125I]LSD labels 5-HT1C recognition sites in pig choroid plexusmembranes. Comparison with [3H]mesulergine and [3H]5-HT binding”. HoyerD, Srivatsa S, Pazos A, Engel G and J M Palacios, Neurosci Lett. 1986,69(3):269-74

“Serotonin receptors in the human brain. I. Characterization andautoradiographic localization of 5-HT1A recognition sites. Apparentabsence of 5-HT1B recognition sites” Hoyer D, Pazos A, Probst A and J MPalacios, Brain Res. 1986, 376(1):85-96

“Serotonin receptors in the human brain. II. Characterization andautoradiographic localization of 5-HT1C and 5-HT2 recognition sites”Hoyer D, Pazos A, Probst A and J M Palacios, Brain Res. 1986,376(1):97-107

“Serotonin receptors in the human brain—III. Autoradiographic mapping ofserotonin-1 receptors” Pazos A, Probst A, and J M Palacios,Neuroscience. 1987, 21(1):97-122

BIBLIOGRAPHY

-   Altar C A, Wasley A M, Neale F F et al, 1986, Typical and atypical    antipsychotic occupancy of D-2 and S-2 receptors: An    autoradiographic analysis in rat brain. Brain Res. Bull. 16:    517-525.-   Andreasen N C, 1982, Negative symptoms in schizophrenia. Definition    and reliability. Arch Gen Psychiatry; 39(7):784-8.-   Arvanitis L A, Miller B G, 1997, Multiple fixed doses of “Seroquel”    (quetiapine) in patients with acute exacerbation of schizophrenia: a    comparison with haloperidol and placebo. The Seroquel Trial 13 Study    Group. Biol Psychiatry. 42(4):233-46.-   Azorin J M, Spiegel R, Remington G, Vanelle J M, Pere J J, Giguere    M, Bourdeix, 2001, A double-blind comparative study of clozapine and    risperidone in the management of severe chronic schizophrenia. Am J    Psychiatry. 158(8):1305-13.-   Baron M, 2001, Genetics of schizophrenia and the new millennium:    progress and pitfalls. Am J Hum Genet. 68(2):299-312.-   Bassett A S, Chow E W, Waterworth D M, Brzustowicz L, 2001, Genetic    insights into schizophrenia. Can J Psychiatry. 46(2):131-7.-   Berg K A, Clarke W P, Sailstad C, Saltzman A, Maayani S, 1994,    Signal transduction differences between 5-hydroxytryptamine type 2A    and type 2C receptor systems. Mol Pharmacol. 46(3):477-84.-   Berg K A, Maayani S, Clarke W P, 1996, 5-hydroxytryptamine2C    receptor activation inhibits 5-hydroxytryptamine1B-like receptor    function via arachidonic acid metabolism. Mol Pharmacol.    50(4):1017-23.-   Berg K A, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke W P,    1998, Effector pathway-dependent relative efficacy at serotonin type    2A and 2C receptors: evidence for agonist-directed trafficking of    receptor stimulus. Mol Pharmacol. 54(1):94-104.-   Berg K A, Stout B D, Cropper J D, Maayani S, Clarke W P, 1999, Novel    actions of inverse agonists on 5-HT2C receptor systems. Mol    Pharmacol. May; 55(5):863-72.-   Bolden C, Cusack B and Richelson E, 1992, Antagonism by    antimuscarinic and neuroleptic compounds at the five cloned human    muscarinic cholinergic receptors expressed in chinese hamster ovary    cells. J. Pharmacol. Exp. Ther. 260: 576-580.-   Bunney B G, Bunney W E and A Carlsson, 2000, Schizophrenia and    Glutamate: An Update, Psychopharmacology—The Fourth Generation of    Progress, The American College of Neuropsychopharmacology website:    http://www.acnp.org/g4/4thgen.php-   Bymaster F P, Calligaro D O, Falcone J F, et al, 1996, Radioreceptor    binding profile of the atypical antipsychotic olanzapine.    Neuropsychopharmacol. 14: 87-96.-   Canton H, Verriele L, Colpaert F C, 1990, Binding of typical and    atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine    potently interacts with 5-HT1C sites. Eur J. Pharmacol. 191(1):93-6.-   Carlsson A, 1988, The current status of the dopamine hypothesis of    schizophrenia. Neuropsychopharmacol. 1:179-186.-   Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson    M L, 2001, Interactions between monoamines, glutamate, and GABA in    schizophrenia: new evidence. Annu Rev Pharmacol Toxicol. 41:237-60.-   Carlsson A, Waters N, Waters S, Carlsson M L, 2000, Network    interactions in schizophrenia—therapeutic implications. Brain Res    Brain Res Rev. 31(2-3):342-9.-   Casey D E, 1994, Motor and mental aspects of acute extrapyramidal    syndromes. Acta Psychiatr Scand Suppl.380:14-20.-   Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B, 2001,    Effectiveness of second-generation antipsychotics in patients with    treatment-resistant schizophrenia: a review and meta-analysis of    randomised trials. Am J Psychiatry. 158(4):518-26.-   Conley R R, Mahmoud R, 2001, A randomized double-blind study of    risperidone and olanzapine in the treatment of schizophrenia or    schizoaffective disorder. Am J Psychiatry 158(5):765-74.-   Corbett R, Hartman H B, Kerman L L, et al, 1993, Effects of atypical    antipsychotic agents on social behaviour in rodents. Pharmacol.    Biochem. Beh. 45: 9-17.-   Creese I, Burt D R and Snyder S H, 1976, Dopamine receptor binding    predicts clinical and pharmacological potencies of    anti-schizophrenic drugs. Science 192: 481-483.-   Creese I, Burt D R, Snyder S H, 1976, Dopamine receptor binding    predicts clinical and pharmacological potencies of antischizophrenic    drugs. Science. 192(4238):481-3.-   Cuesta M J, Peralta V, Zarzuela A, 2001, Effects of olanzapine and    other antipsychotics on cognitive function in chronic schizophrenia:    a longitudinal study. Schizophr Res. 48(1):17-28.-   Dean B, 2000, Signal transmission, rather than reception, is the    underlying neurochemical abnormality in schizophrenia. Aust N Z J    Psychiatry. 34(4):560-9.-   Deniker, P. (1983) Discovery of the clinical use of neuroleptics. In    Discoveries in Pharmacology (eds M. J. Parnham & J. Bruinvels), Vol    1, pp. 163-180. Amsterdam: Elsevier Science Publishers.-   Du L, Faludi G, Palkovits M, Bakish D, Hrdina P D, 2001,    Serotonergic genes and suicidality. Crisis 22(2):54-60.-   Farde L, Nordstrom A L, Wiesel F A, Pauli S, Halldin C, Sedvall G,    1992, Positron emission tomographic analysis of central D1 and D2    dopamine receptor occupancy in patients treated with classical    neuroleptics and clozapine. Relation to extrapyramidal side effects.    Arch Gen Psychiatry. 49(7):538-44.-   Farde L, Wiesel F-A, Nordstrom A-L, et al, 1989, D₁ and D₂-dopamine    receptor occupancy during treatment with conventional and atypical    neuroleptics. Psychopharmacol. 99 S28-S31.-   Glatt C E, Snowman A M, Sibley D R, et al, 1995, Clozapine selective    labeling of sites resembling 5HT6 serotonin receptors may reflect    psychoactive profile. Mol. Medicine 1: 398-406.-   Goldberg T E, Kelsoe J R, Weinberger D R, Pliskin N H, Kirwin P D,    Berman K F, 1988, Performance of schizophrenic patients on putative    neuropsychological tests of frontal lobe function. Int J. Neurosci.    42(1-2):51-8.-   Goldstein J M, Link B G, 1988, Gender and the expression of    schizophrenia. J Psychiatr Res.; 22(2):141-55.-   Goldstein J M, Seidman L J, Goodman J M, Koren D, Lee H, Weintraub    S, Tsuang M T, 1998, Are there sex differences in neuropsychological    functions among patients with schizophrenia? Am J Psychiatry.    155(10):1358-64.-   Goldstein J M, Seidman L J, Santangelo S, Knapp P H, Tsuang M T,    1994, Are schizophrenic men at higher risk for developmental    deficits than schizophrenic women? Implications for adult    neuropsychological functions. J Psychiatr Res. 28(6):483-98.-   Green M F, Marshall B D Jr, Wirshing W C, Ames D, Marder S R,    McGurk S. Kern R S, Mintz J. 1997, Does risperidone improve verbal    working memory in treatment-resistant schizophrenia? Am J    Psychiatry. 154(6):799-804.-   Hagger C, Buckley P. Kenny J T, Friedman L, Ubogy D, Meltzer H Y,    1993, Improvement in cognitive functions and psychiatric symptoms in    treatment-refractory schizophrenic patients receiving clozapine.    Biol Psychiatry. 34(10):702-12.-   Hoyer D, Engel G and HO Kalkman, 1985, Molecular pharmacology of    5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes:    radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT,    (−)[125I]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin.    Eur J. Pharmacol. 118(1-2):13-23.-   Hoyer D, Pazos A, Probst A and J M Palacios, 1986, Serotonin    receptors in the human brain. I. Characterization and    autoradiographic localization of 5-HT1A recognition sites. Apparent    absence of 5-HT1B recognition sites. Brain Res. 376(1):85-96.-   Hoyer D, Pazos A, Probst A and J M Palacios, 1986, Serotonin    receptors in the human brain. II. Characterization and    autoradiographic localization of 5-HT1C and 5-HT2 recognition sites.    Brain Res. 376(1):97-107.-   Hoyer D, Srivatsa S, Pazos A, Engel G and J M Palacios, 1986,    [125I]LSD labels 5-HT1C recognition sites in pig choroid plexus    membranes. Comparison with [3H]mesulergine and [3H]5-HT binding.    Neurosci Lett. 69(3):269-74.-   Javitt D C, 2001, Management of negative symptoms of schizophrenia.    Curr Psychiatry Rep. 3(5):413-7.-   Kanba S, Suzuki E, Nomura S, et al, 1994, Affinity of neuroleptics    for D₁ receptor of human brain striatum. J. Psych. Neurosci., 19:    265-269.-   Kane J M, Woerner M G, Pollack S, et al, 1993, Does clozapine cause    tardive dyskinesia? J. Clin. Psychiatry 54: 327-330.-   Kay S R, Opler L A, Spitzer R L, Williams J B, Fiszbein A, Gorelick    A, 1991, SCID-PANSS: two-tier diagnostic system for psychotic    disorders. Compr Psychiatry. 32(4):355-61.-   Kongsamut S, Roehr J E, Cai J, et al, 1996, Iloperidone binding to    human and rat dopamine and 5-HT receptors. Eur. J. Pharmacol.    317:417-423.-   Kurachi M, Matsui M, Kiba K, Suzuki M, Tsunoda M, Yamaguchi N, 1994,    Limited visual search on the WAIS Picture Completion test in    patients with schizophrenia. Schizophr Res. 12(1):75-80.-   Leucht S, Pitschel-Walz G, Abraham D, Kissling W, 1999, Efficacy and    extrapyramidal side-effects of the new antipsychotics olanzapine,    quetiapine, risperidone, and sertindole compared to conventional    antipsychotics and placebo. A meta-analysis of randomised controlled    trials. Schizophr Res. 35(1):51-68.-   Lewis D A, Lieberman J A, 2000, Catching up on schizophrenia:    natural history and neurobiology. Neuron 28(2):325-34.-   Lewis D A, Pierri J N, Volk D W, Melchitzky D S, Woo T U, 1999,    Altered GABA neurotransmission and prefrontal cortical dysfunction    in schizophrenia. Biol Psychiatry. 46(5):616-26.-   Lewis R, Bagnall A, Leitner M, 2000, Sertindole for schizophrenia.    Cochrane Database Syst Rev. 2:CD001715.-   Leysen J, 2000, Novel Atypical Antipsychotics, Atypical    Antipsychotics, Eds. B A Ellenbroek and A R Cools, Series Eds. M J    Parnham and J Bruinvels, Birkhauser Verlag, Basel-Boston-Berlin.-   Leysen J E, Gommeren W, Eens A, de Chaffoy de Courcelles D, Stoof J    C, Janssen P A, 1988, Biochemical profile of risperidone, a new    antipsychotic. J Pharmacol Exp Ther. 247(2):661-70.-   Leysen J E, Gommeren W, Mertens J, et al, 1993, Comparison of in    vitro binding properties of a series of dopamine antagonists and    agonists for cloned human dopamine D2S and D2L receptors and for D₂    receptors in rat striatal and mesolimbic tissues, using [125I]    2′-iodospiperone. Psychopharmacol. 110: 27-36.-   Lieberman J A, 1993, Understanding the mechanism of action of    atypical antipsychotic drugs. a review of compounds in use and    development. Brit. J. Pharmacol. 163: 7-18.-   Mahurin R K, Velligan D I, Miller A L, 1998, Executive-frontal lobe    cognitive dysfunction in schizophrenia: a symptom subtype analysis.    Psychiatry Res. 79(2):139-49.-   Malmberg A, Jackson D M, Eriksson A M, et al, 1993, Unique Binding    Characteristics of Antipsychotic Agents Interacting with Human    Dopamine D_(2A), D_(2B), and D₃ Receptors. Mol. Pharmacol. 43:    749-754.-   Matz R, Rick W, Oh D et al, 1974, Clozapine-A potential    antipsychotic agent without extrapyramidal manifestations. Curr.    Ther. Research 16: 687-695.-   Meltzer H Y, 1994, An overview of the mechanism of action of    clozapine. J Clin Psychiatry. 55 Suppl B:47-52.-   Meltzer H Y, 1996, Pre-clinical pharmacology of atypical    antipsychotic drugs: a selective review. Brit. J. Psychiatry 168:    23-31.-   Meltzer H Y, 1998, Suicide in schizophrenia: risk factors and    clozapine treatment. J Clin Psychiatry 59 Suppl 3:15-20.-   Meltzer H Y, 1999, The role of serotonin in antipsychotic drug    action. Neuropsychopharmacology. 21(2 Suppl):106S-115S.-   Meltzer H Y, Bastani B, Young K K, et al, 1989a, A prospective study    of clozapine in treatment-resistant schizophrenic patients.    Psychopharmacol. 238: 332-339.-   Meltzer H Y, Matsubara S and Lee J-C, 1989b, Classification of    typical and atypical antipsychotic drugs on the basis of dopamine    D-1, D-2 and serotonin pKi values. J. Pharmacol. Exp. Ther. 251:    238-246.-   Meltzer H Y, Matsubara S, Lee J C, 1989, The ratios of serotonin2    and dopamine2 affinities differentiate atypical and typical    antipsychotic drugs. Psychopharmacol Bull. 25(3):390-2.-   Meltzer H Y, McGurk S R, 1999, The effects of clozapine,    risperidone, and olanzapine on cognitive function in schizophrenia.    Schizophr Bull. 25(2):233-55.-   Meltzer H Y, Thompson P A, Lee M A, Ranjan R, 1996, Neuropsychologic    deficits in schizophrenia: relation to social function and effect of    antipsychotic drug treatment. Neuropsychopharmacology. 14(3    Suppl):27S-33S.-   Meltzer, H Y, Atypical Antipsychotic Drugs, 2000,    Psychopharmacology—The Fourth Generation of Progress, The American    College of Neuropsychopharmacology website:    http://www.acnp.org/g4/4thgen.php-   Niswender C M, Herrick-Davis K, Dilley G E, Meltzer H Y, Overholser    J C, Stockmeier C A, Emeson R B, Sanders-Bush E, 2001, RNA editing    of the human serotonin 5-HT2C receptor. alterations in suicide and    implications for serotonergic pharmacotherapy.    Neuropsychopharmacology. 24(5):478-91.-   O'Donovan M C, Owen M J, 1999, Candidate-gene association studies of    schizophrenia. Am J Hum Genet. 65(3):587-92.-   Olney J W, Newcomer J W, Farber N B, 1999, NMDA receptor    hypofunction model of schizophrenia. J Psychiatr Res. 33(6):523-33.-   Pandey G N, 1997, Altered serotonin function in suicide. Evidence    from platelet and neuroendocrine studies. Ann N Y Acad. Sci.    836:182-200.-   Pazos A and J M Palacios, 1985, Quantitative autoradiographic    mapping of serotonin receptors in the rat brain. I. Serotonin-1    receptors. Brain Res. 346(2):205-30.-   Pazos A, Hoyer D and J M Palacios, 1985, The binding of serotonergic    ligands to the porcine choroids plexus: characterization of a new    type of serotonin recognition site. Eur J. Pharmacol. 106:539-546.-   Pazos A, Probst A, and J M Palacios, 1987, Serotonin receptors in    the human brain—III. Autoradiographic mapping of serotonin-1    receptors. Neurosci. 21(1):97-122.-   Pezawas L, Quiner S, Moertl D, Tauscher J, Barnas C, Kufferle B,    Wolf R, Kasper S, 2000, Efficacy, cardiac safety and tolerability of    sertindole: a drug surveillance. Int Clin Psychopharmacol.    15(4):207-14.-   Pickar D, Rubinow K, 2001, Pharmacogenomics of psychiatric    disorders. Trends Pharmacol Sci. 22(2):75-83.-   Pilowski L S, Costa D C, Ell P J, et al, 1992, Clozapine, single    photon emission tomography, and the D2 dopamine receptor blockade    hypothesis of schizophrenia. Lancet 340: 199-202.-   Portnoff L A, Yesavage J A, Acker M B, 1981, Visual search    performance by paranoid and chronic undifferentiated schizophrenics.    Percept Mot Skills 53(2):411-8.-   Purdon S E, Jones B D, Stip E, Labelle A, Addington D, David S R,    Breier A, Tollefson G D, 2000, Neuropsychological change in early    phase schizophrenia during 12 months of treatment with olanzapine,    risperidone, or haloperidol. The Canadian Collaborative Group for    research in schizophrenia. Arch Gen Psychiatry. 57(3):249-58.-   Purdon S E, Malla A, Labelle A, Lit W, 2001, Neuropsychological    change in patients with schizophrenia after treatment with    quetiapine or haloperidol. J Psychiatry Neurosci. 26(2):137-49.-   Reyntjens A, Gelders Y G, Hoppenbrouwers-M-LJA, Vanden-Bussche G,    1986, Thymosthenic effects of ritanserin (R 55667), a centrally    acting serotonin-S-2 receptor blocker. Drug Dev. Research    8(1-4):205-211.-   Richelson E and Nelson A, 1984, Antagonism by neuroleptics of    neurotransmitter receptors of normal human brain in vitro. Eur. J.    Pharmacol. 103: 197-204.-   Richelson E, 1996, Preclinical pharmacology of neuroleptics: focus    on new generation compounds. J. Clin. Psychiatry 57: 4-11.-   Roth B L, Ciaranello R D and Meltzer H Y, 1992, Binding of typical    and atypical antipsychotic agents to transient expressed 5-HT_(1C)    receptors. J. Pharmacol. Exp. Ther. 260, 1361-1365.-   Roth B L, Craigo S C, Choudhary M S, et al, 1994, Binding of typical    and atypical antipsychotic agents to 5-hydroxy-tryptamine-6 and    5-hydroxytryptamine-7 receptors. J. Pharmacol. Exp. Ther.    268(3):1403-1408.-   Roth B L, Tandra S, Burgess L H, et al, 1995, D₄ Dopamine receptor    binding affinity does not distinguish between typical and atypical    antipsychotic drugs. Psychopharmacol. 120: 365-368.-   Sauriol L, Laporta M, Edwardes M D, Deslandes M, Ricard N, Suissa S,    2001, Meta-analysis comparing newer antipsychotic drugs for the    treatment of schizophrenia: evaluating the indirect approach. Clin    Ther. 23(6):942-56.-   Schotte A, Janssen P F M, Gommeren W, et al, 1996, Risperidone    compared with new and reference antipsychotic drugs: in vitro and in    vivo receptor binding. Psychopharmacol. 124: 57-73.-   Seeger T F, Seymour P A, Schmidt A W, et al, 1995, Ziprasidone    (CP-88, 059): a new antipsychotic with combined dopamine and    serotonin receptor antagonist activity. J. Pharmacol. Exp. Ther.    275: 101-113.-   Seeman P and Lee T, 1975, Antipsychotic drugs: direct correlation    between clinical potency and presynaptic action on dopamine neurons.    Science 188: 1217-1219.-   Siris S G, 2001, Suicide and schizophrenia. J Psychopharmacol.    15(2):127-35.-   Szewczak M R, Corbett R, Rush D K, et al, 1995, The pharmacological    profile of iloperidone, a novel atypical anti-psychotic agent. J.    Pharmacol. Exp. Ther. 274: 1404-1413.-   Taylor D M, McAskill R, 2000, Atypical antipsychotics and weight    gain—a systematic review. Acta Psychiatr Scand. 101(6):416-32.-   Tran P V, Hamilton S H, Kuntz A J, Potvin J H, Andersen S W, Beasley    C Jr, Tollefson G D, 1997, Double-blind comparison of olanzapine    versus risperidone in the treatment of schizophrenia and other    psychotic disorders. J Clin Psychopharmacol. 17 (5):407-18.-   Tsuang M T, Stone W S, Faraone S V, 2001, Genes, environment and    schizophrenia. Br J Psychiatry Suppl. 40:S18-24.-   van Tol HHM, Bunzow J R, Guan H-C, et al, 1991, Cloning of the gene    for a human dopamine D4 receptor with high affinity for the    antipsychotic clozapine. Nature 350: 610-615.-   Waddington J L and J F Quinn, 2000, From first to second generation    antipsychotics. Atypical Antipsychotics, Eds. BA Ellenbroek and AR    Cools, Series Eds. MJ Parnham and J Bruinvels, Birkhauser Verlag,    Basel-Boston-Berlin, pp: 19-33-   Velligan D I, Newcomer J, Pultz J, Csernansky J, Hoff A L, Mahurin    R, Miller A L, 2002, Does cognitive function improve with quetiapine    in comparison to haloperidol? Schizophr Res. 53(3):239-48.-   Wander T J, Nelson A, Okazaki H, et al, 1987, Antagonism by    neuroleptics of serotonin 5-HT1A and 5-HT₂ receptors of normal human    brain in vitro. Eur J. Pharmacol. 143: 279-282.-   Weinberger D R, 2000, Neurodevelopmental Perspectives on    Schizophrenia, Psychopharmacology—The Fourth Generation of Progress,    The American College of Neuropsychopharmacology website:    http://www.acnp.org/g4/4thgen.php-   Wetterling T, 2001, Bodyweight gain with atypical antipsychotics. A    comparative review. Drug Saf. 24(1):59-73.-   Wirshing D A, Wirshing W C, Kysar L, Berisford M A, Goldstein D,    Pashdag J, Mintz J, Marder S R, 1999, Novel antipsychotics:    comparison of weight gain liabilities. J Clin Psychiatry    60(6):358-63.-   Yagaloff K A, Lozano G, Van Dyke T, Levine A and P R Hartig, 1986,    Serotonin 5-HT1C receptors are expressed at high density on choroid    plexus tumors from transgenic mice. Brain Res. 385(2):389-94.

1-19. (canceled)
 20. A method for determining the suitability of acandidate compound for use in the treatment of negative symptoms ofand/or cognitive dysfunction in schizophrenia, refractory schizophrenia,suicidality or mild cognitive impairment which comprises: a) assessingthe affinity of the compound at the 5-HT2C receptor; b) assessing theaffinity of the compound at at least two other major sites of saidcompound interaction; c) applying the assessed affinities to thefollowing formula: ${\frac{X}{A} + \frac{X}{B}} = Y$ wherein: X is theaffinity of a compound for interaction at the 5-HT2C receptor and A andB are the average affinity values of a compound for interaction at twomajor sites other than the 5-HT2C receptor; and selecting compounds inwhich Y≧1.80 as suitable compounds for the treatment of cognitivedysfunction in and/or negative symptoms of schizophrenia, refractoryschizophrenia, suicidality or mild cognitive impairment, provided that:(a) for the treatment of cognitive dysfunction in and/or negativesymptoms of schizophrenia or refractory schizophrenia, the compoundselected is other than ritanserin, clozapine, fluperlapine, loxapine,ORG-5222, pipamperone, sertindole, olanzapine, zotepine or ziprasidone;(b) for the indications cognitive dysfunction in schizophrenia or mildcognitive impairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and (c) forthe treatment of schizophrenic suicidality, the compound selected isother than clozapine.
 21. The method of claim 20 in which A and B aredifferent and are independently selected from the group consisting ofthe 5-HT_(1A), 5-HT_(2A), 5-HT₃, 5-HT₆, 5-HT₇, D₁, D₂-S, D₂-L, D₃, D₄,D₅ M₁, M₂, M₃, M₄, M₅, mACh, α₁, α₂, H₁ or sigma receptors.
 22. Themethod of claim 21 in which A is the value for affinity at the 5-HT2Areceptor.
 23. The method of claim 21 in which B is the value foraffinity at the D2 receptor.
 24. The method of claim 20 in which thecompound selected has Y≧2.00.
 25. A therapeutic product comprising a5-HT2C receptor antagonist and a typical anti-psychotic, said productbeing a combined preparation for the treatment of schizophrenia,suicidality or mild cognitive impairment, wherein said antagonist andsaid anti-psychotic are administered simultaneously, separately orsequentially.
 26. A therapeutic product in which the 5-HT2C receptorantagonist is identifiable by the method of claim
 20. 27. A method forthe treatment of a patient suffering from symptoms associated with acondition selected from the group consisting of negative symptoms ofschizophrenia, cognitive dysfunction in schizophrenia, refractoryschizophrenia, suicidality and mild cognitive impairment with apharmaceutically effective amount of a compound having a relative 5-HT2Caffinity of ≧1.80, wherein the relative 5HT2C affinity is determinedaccording to the method of claim 20 with the proviso that: (a) when thecondition is selected from the group consisting of negative symptoms ofschizophrenia, cognitive dysfunction in schizophrenia and refractoryschizophrenia, the compound is other than ritanserin, clozapine,fluperlapine, loxapine, ORG-5222, pipamperone, sertindole, olanzapine,zotepine or ziprasidone; (b) when the condition is selected from thegroup consisting of cognitive dysfunction in schizophrenia and mildcognitive impairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and (c)when the condition is schizophrenic suicidality, the compound is otherthan clozapine.
 28. A method according to claim 27 wherein the conditionis refractory schizophrenia, with the proviso that the compound is otherthan ritanserin, clozapine, fluperlapine, loxapine, ORG-5222,pipamperone, sertindole, olanzapine, zotepine or ziprasidone.
 29. Amethod according to claim 27 wherein the condition is suicidality, withthe proviso that, when the suicidality is in a schizophrenic patient,the compound is other than clozapine.
 30. A method according to claim29, wherein the suicidality is in a schizophrenic patient.
 31. A methodaccording to claim 27 wherein the condition is mild cognitive impairmentwith the proviso that the compound is other than deramciclane orN-desmethylderamciclane.
 32. A method according to claim 27 wherein thecompound is as described in a publication selected from the groupconsisting of WO 97/16429, WO 97/44334, U.S. Pat. No. 5,010,078, EP161,218, EP401,707, EP526,434, DE02834114, EP 210,893, U.S. Pat. No.3,580,916, U.S. Pat. No. 5,043,341, EP 620,222, EP 208,235, EP 437,790,DE 02614406, U.S. Pat. No. 4,338,317, EP 271,013, EP 110,435, EP398,326, WO 92/05170, WO 95/01976, WO 96/23783, WO 98/04289, WO97/48700, WO 00/48602, WO 00/26186, WO 99/58490, WO 99/52517, WO99/51237, WO 99/46245, WO 99/43319, WO 99/33841, WO 99/33840, WO99/25356, WO 99/09017, WO 99/03833, WO 99/00119, WO 98/56367, WO98/52943, WO 98/50358, WO 98/50346, WO 98/50343, WO 98/41527, WO98/38165, WO 98/30561, WO 98/30546, WO 98/24785, WO 98/21958, WO98/04261, WO 97/48699, WO 97/41858, WO 97/39001, WO 97/37989, WO97/20845, WO 97/12880, WO 97/08167, WO 97/06155, WO 97/00872, WO96/39382, WO 96/30366, WO 96/24351, WO 96/23769, WO 96/18629, WO96/14320, WO 96/11930, WO 96/11929, WO 96/02537, WO 95/29177, WO95/25731, WO 95/24194, WO 95/21844, WO 95/18117, WO 95/12591, WO994/22871, WO 94/18958, WO 94/18182, WO 94/18170, WO 94/14801, WO94/04533, WO 94/02462, WO 93/18028, WO 93/18026, WO 93/16081, WO93/16051, WO 93/14758, WO 93/12790, WO 92/15302, WO 92/10192, WO91/18602, WO 01/68585, WO 01/68067, WO 01/52855, WO 01/38329, WO01/26621, WO 01/25229, WO 01/19371, WO 00/76984, WO 00/68181, WO00/63185, WO 00/62782, WO 00/61129, WO 00/61128, WO 00/37068, WO00/06165, U.S. Pat. No. 6,143,325, U.S. Pat. No. 5,854,248, U.S. Pat.No. 5,739,336, U.S. Pat. No. 5,693,645, U.S. Pat. No. 5,674,875, U.S.Pat. No. 5,498,618, U.S. Pat. No. 5,371,093, U.S. Pat. No. 5,266,571,U.S. Pat. No. 5,116,852, U.S. Pat. No. 5,106,855, U.S. Pat. No.5,030,656, U.S. Pat. No. 5,013,735, U.S. Pat. No. 4,985,352, U.S. Pat.No. 4,914,107, U.S. Pat. No. 4,914,100, U.S. Pat. No. 4,906,639, U.S.Pat. No. 4,902,691, U.S. Pat. No. 4,891,376, U.S. Pat. No. 4,847,261, JP13220375, JP 12204040, JP 11171865, JP 11080155, JP 10316634, JP10077271, JP 09040646, JP 08053416, JP 08040999, JP 07228573, JP07179337, JO 00158067, GB 02303303, GB 02301774, EP 01118610, EP1070716, EP 01052245, EP 01000944, EP 00905136, EP 00797995, EP00797994, EP 00769297, EP 00749971, EP 00749967, EP 00718299, EP00700905, EP 00686393, EP 00682015, EP 0661266, EP 00657426, EP006554440, EP 00613898, EP 00596449, EP 00559569, EP 00545120, EP00522226, EP 00511074, EP 00511073, EP 00493687, EP 00484988, EP00465398, EP 00452074, EP 00389352, EP 00388081, EP 00384228, EP00379308, EP 00378468, EP 00375297, EP 00374042, EP 00373998, EP00363963, EP 00354030, EP 00337136, EP 00332528, EP 00320983, EP00218433 and EP
 00145494. 33. A method according to claim 27 in whichthe compound is selected from the group consisting of AHR-16303B (AHRobins Co. Inc), AP-792 and AT-1015 (Ajinomoto Co. Inc.), BMS-181102(Bristol Myers Squibb), CV-5197 (Takeda Chemical Industries Ltd),dotarizine (Ferrer Internacional SA), E-2101 (Eisai Co Ltd), eltoprazine(Solvay SA), emopamil (Knoll AG), HT-90B (Chugai Pharmaceutical Co Ltd),ICI-169369 and ICI-170809 (Zeneca Group plc), LU-26042 and LU-29066 (HLundbeck A/S), NPC-18166 (Scios Inc), Org-38457 (NV Organon), pelanserin(Cinvestav), perbufylline (Siegfried Group), SB-206553 and SB-242084(SmithKline Beecham), SR-46615A (Sanofi Recherche SA), SUN-9221 (SuntoryLtd) tropoxin (Russian Academy Medical Science) and YM-992 (YamanouchiPharmaceutical Co Ltd).
 34. A method according to claim 27 in which thecompound is selected from the group consisting of Ro-60-0759, RS-102221,SDZ-SER-082, ICI-169369, deramciclane, N-desmethyl-deramciclane,amesergide, sergolexole, CGS-18102A and LU-26042.
 35. A method accordingto claim 34 in which the compound is selected from the group consistingof deramciclane, N-desmethyl-deramciclane, amesergide, sergolexole,CGS-18102A and LU-26042.
 36. A method according to claim 27 wherein thecondition is suicidality or mild cognitive impairment and wherein thecompound is selected from the group consisting of ritanserin, clozapine,fluperlapine, loxapine, ORG-5222, pipamperone, sertindole, olanzapine,zotepine and ziprasidone, with the proviso that when the suicidality isin a schizophrenic patient, the compound is other than clozapine.
 37. Amethod for the treatment of a patient suffering from symptoms associatedwith a condition selected from the group consisting of refractoryschizophrenia, suicidality and mild cognitive impairment with apharmaceutically effective amount of a 5-HT2C receptor antagonist withthe proviso that: (a) when the condition is refractory schizophrenia,the 5-HT2C receptor antagonist is other than ritanserin, clozapine,fluperlapine, loxapine, ORG-5222, pipamperone, sertindole, olanzapine,zotepine or ziprasidone; (b) when the condition is mild cognitiveimpairment, the 5-HT2C receptor antagonist is other than(1R,2S,4R)-(−)-2-phenyl-2-(dimethylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane,(1R,2S,4R)-(−)-2-phenyl-2-(methylaminoethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptaneand pharmaceutically acceptable acid addition salts thereof; and (c)when the condition is schizophrenic suicidality, the 5-HT2C receptorantagonist is other than clozapine.
 38. A method according to claim 37wherein the condition is refractory schizophrenia, with the proviso thatthe antagonist is other than ritanserin, clozapine, fluperlapine,loxapine, ORG-5222, pipamperone, sertindole, olanzapine, zotepine orziprasidone.
 39. A method according to claim 37 wherein the condition issuicidality, with the proviso that, when the suicidality is in aschizophrenic patient, the 5-HT2C receptor antagonist is other thanclozapine.
 40. A method according to claim 39, wherein the suicidalityis in a schizophrenic patient.
 41. A method according to claim 37wherein the condition is mild cognitive impairment with the proviso thatthe antagonist is other than deramciclane or N-desmethylderamciclane.42. A method according to claim 37 wherein the 5-HT2C receptorantagonist is as described in a publication selected from the groupconsisting of WO 97/16429, WO 97/44334, U.S. Pat. No. 5,010,078, EP161,218, EP 401,707, EP 526,434, DE 02834114, EP210,893, U.S. Pat. No.3,580,916, U.S. Pat. No. 5,043,341, EP620,222, EP208,235, EP 437,790, DE02614406, U.S. Pat. No. 4,338,317, EP 271,013, EP 110,435, EP 398,326,WO 92/05170, WO 95/01976, WO 96/23783, WO 98/04289, WO 97/48700, WO00/48602, WO 00/26186, WO 99/58490, WO 99/52517, WO 99/51237, WO99/46245, WO 99/43319, WO 99/33841, WO 99/33840, WO 99/25356, WO99/09017, WO 99/03833, WO 99/00119, WO 98/56367, WO 98/52943, WO98/50358, WO 98/50346, WO 98/50343, WO 98/41527, WO 98/38165, WO98/30561, WO 98/30546, WO 98/24785, WO 98/21958, WO 98/04261, WO97/48699, WO 97/41858, WO 97/39001, WO 97/37989, WO 97/20845, WO97/12880, WO 97/08167, WO 97/06155, WO 97/00872, WO 96/39382, WO96/30366, WO 96/24351, WO 96/23769, WO 96/18629, WO 96/14320, WO96/11930, WO 96/11929, WO 96/02537, WO 95/29177, WO 95/25731, WO95/24194, WO 95/21844, WO 95/18117, WO 95/12591, WO9 94/22871, WO94/18958, WO 94/18182, WO 94/18170, WO 94/14801, WO 94/04533, WO94/02462, WO 93/18028, WO 93/18026, WO 93/16081, WO 93/16051, WO93/14758, WO 93/12790, WO 92/15302, WO 92/10192, WO 91/18602, WO01/68585, WO 01/68067, WO 01/52855, WO 01/38329, WO 01/26621, WO01/25229, WO 01/19371, WO 00/76984, WO 00/68181, WO 00/63185, WO00/62782, WO 00/61129, WO 00/61128, WO 00/37068, WO 00/06165, U.S. Pat.No. 6,143,325, U.S. Pat. No. 5,854,248, U.S. Pat. No. 5,739,336, U.S.Pat. No. 5,693,645, U.S. Pat. No. 5,674,875, U.S. Pat. No. 5,498,618,U.S. Pat. No. 5,371,093, U.S. Pat. No. 5,266,571, U.S. Pat. No.5,116,852, U.S. Pat. No. 5,106,855, U.S. Pat. No. 5,030,656, U.S. Pat.No. 5,013,735, U.S. Pat. No. 4,985,352, U.S. Pat. No. 4,914,107, U.S.Pat. No. 4,914,100, U.S. Pat. No. 4,906,639, U.S. Pat. No. 4,902,691,U.S. Pat. No. 4,891,376, U.S. Pat. No. 4,847,261, JP 13220375, JP12204040, JP 11171865, JP 11080155, JP 10316634, JP 10077271, JP09040646, JP 08053416, JP 08040999, JP 07228573, JP 07179337, JO00158067, GB 02303303, GB 02301774, EP 01118610, EP 1070716, EP01052245, EP 01000944, EP 00905136, EP 00797995, EP 00797994, EP00769297, EP 00749971, EP 00749967, EP 00718299, EP 00700905, EP00686393, EP 00682015, EP 0661266, EP 00657426, EP 006554440, EP00613898, EP 00596449, EP 00559569, EP 00545120, EP 00522226, EP00511074, EP 00511073, EP 00493687, EP 00484988, EP 00465398, EP00452074, EP 00389352, EP 00388081, EP 00384228, EP 00379308, EP00378468, EP 00375297, EP 00374042, EP 00373998, EP 00363963, EP00354030, EP 00337136, EP 00332528, EP 00320983, EP 00218433 and EP00145494.
 43. A method according to claim 37 in which the 5-HT2Creceptor antagonist is selected from the group consisting of AHR-16303B(AH Robins Co. Inc), AP-792 and AT-1015 (Ajinomoto Co. Inc.), BMS-181102(Bristol Myers Squibb), CV-5197 (Takeda Chemical Industries Ltd),dotarizine (Ferrer Internacional SA), E-2101 (Eisai Co Ltd), eltoprazine(Solvay SA), emopamil (Knoll AG), HT-90B (Chugai Pharmaceutical Co Ltd),ICI-169369 and ICI-170809 (Zeneca Group plc), LU-26042 and LU-29066 (HLundbeck A/S), NPC-18166 (Scios Inc), Org-38457 (NV Organon), pelanserin(Cinvestav), perbufylline (Siegfried Group), SB-206553 and SB-242084(SmithKline Beecham), SR-46615A (Sanofi Recherche SA), SUN-9221 (SuntoryLtd) tropoxin (Russian Academy Medical Science) and YM-992 (YamanouchiPharmaceutical Co Ltd).
 44. A method according to claim 37 in which the5-HT2C receptor antagonist is selected from the group consisting ofRo-60-0759, RS-102221, SDZ-SER-082, ICI-169369, deramciclane,N-desmethyl-deramciclane, amesergide, sergolexole, CGS-18102A andLU-26042.
 45. A method according to claim 44 in which the 5-HT2Creceptor antagonist is selected from the group consisting ofderamciclane, N-desmethyl-deramciclane, amesergide, sergolexole,CGS-18102A and LU-26042.
 46. A method according to claim 37 wherein thecondition is suicidality or mild cognitive impairment and wherein the5-HT2C receptor antagonist is selected from the group consisting ofritanserin, clozapine, fluperlapine, loxapine, ORG-5222, pipamperone,sertindole, olanzapine, zotepine and ziprasidone, with the proviso thatwhen the suicidality is in a schizophrenic patient, the 5-HT2C receptorantagonist is other than clozapine.
 47. A product according to claim 25in which the 5-HT2C receptor antagonist is as described in a publicationselected from the group consisting of WO 97/16429, WO 97/44334, U.S.Pat. No. 5,010,078, EP 161,218, EP 401,707, EP 526,434, DE 02834114,EP210,893, U.S. Pat. No. 3,580,916, U.S. Pat. No. 5,043,341, EP620,222,EP208,235, EP 437,790, DE 02614406, U.S. Pat. No. 4,338,317, EP 271,013,EP 110,435, EP 398,326, WO 92/05170, WO 95/01976, WO 96/23783, WO98/04289, WO 97/48700, WO 00/48602, WO 00/26186, WO 99/58490, WO99/52517, WO 99/51237, WO 99/46245, WO 99/43319, WO 99/33841, WO99/33840, WO 99/25356, WO 99/09017, WO 99/03833, WO 99/00119, WO98/56367, WO 98/52943, WO 98/50358, WO 98/50346, WO 98/50343, WO98/41527, WO 98/38165, WO 98/30561, WO 98/30546, WO 98/24785, WO98/21958, WO 98/04261, WO 97/48699, WO 97/41858, WO 97/39001, WO97/37989, WO 97/20845, WO 97/12880, WO 97/08167, WO 97/06155, WO97/00872, WO 96/39382, WO 96/30366, WO 96/24351, WO 96/23769, WO96/18629, WO 96/14320, WO 96/11930, WO 96/11929, WO 96/02537, WO95/29177, WO 95/25731, WO 95/24194, WO 95/21844, WO 95/18117, WO95/12591, WO9 94/22871, WO 94/18958, WO 94/18182, WO 94/18170, WO94/14801, WO 94/04533, WO 94/02462, WO 93/18028, WO 93/18026, WO93/16081, WO 93/16051, WO 93/14758, WO 93/12790, WO 92/15302, WO92/10192, WO 91/18602, WO 01/68585, WO 01/68067, WO 01/52855, WO01/38329, WO 01/26621, WO 01/25229, WO 01/19371, WO 00/76984, WO00/68181, WO 00/63185, WO 00/62782, WO 00/61129, WO 00/61128, WO00/37068, WO 00/06165, U.S. Pat. No. 6,143,325, U.S. Pat. No. 5,854,248,U.S. Pat. No. 5,739,336, U.S. Pat. No. 5,693,645, U.S. Pat. No.5,674,875, U.S. Pat. No. 5,498,618, U.S. Pat. No. 5,371,093, U.S. Pat.No. 5,266,571, U.S. Pat. No. 5,116,852, U.S. Pat. No. 5,106,855, U.S.Pat. No. 5,030,656, U.S. Pat. No. 5,013,735, U.S. Pat. No. 4,985,352,U.S. Pat. No. 4,914,107, U.S. Pat. No. 4,914,100, U.S. Pat. No.4,906,639, U.S. Pat. No. 4,902,691, U.S. Pat. No. 4,891,376, U.S. Pat.No. 4,847,261, JP 13220375, JP 12204040, JP 11171865, JP 11080155, JP10316634, JP 10077271, JP 09040646, JP 08053416, JP 08040999, JP07228573, JP 07179337, JO 00158067, GB 02303303, GB 02301774, EP01118610, EP 1070716, EP 01052245, EP 01000944, EP 00905136, EP00797995, EP 00797994, EP 00769297, EP 00749971, EP 00749967, EP00718299, EP 00700905, EP 00686393, EP 00682015, EP 0661266, EP00657426, EP 006554440, EP 00613898, EP 00596449, EP 00559569, EP00545120, EP 00522226, EP 00511074, EP 00511073, EP 00493687, EP00484988, EP 00465398, EP 00452074, EP 00389352, EP 00388081, EP00384228, EP 00379308, EP 00378468, EP 00375297, EP 00374042, EP00373998, EP 00363963, EP 00354030, EP 00337136, EP 00332528, EP00320983, EP 00218433 and EP
 00145494. 48. A product according to claim25 in which the 5-HT2C receptor antagonist is selected from the groupconsisting of AHR-16303B (AH Robins Co. Inc), AP-792 and AT-1015(Ajinomoto Co. Inc.), BMS-181102 (Bristol Myers Squibb), CV-5197 (TakedaChemical Industries Ltd), dotarizine (Ferrer Internacional SA), E-2101(Eisai Co Ltd), eltoprazine (Solvay SA), emopamil (Knoll AG), HT-90B(Chugai Pharmaceutical Co Ltd), ICI-169369 and ICI-170809 (Zeneca Groupplc), LU-26042 and LU-29066 (H Lundbeck A/S), NPC-18166 (Scios Inc),Org-38457 (NV Organon), pelanserin (Cinvestav), perbufylline (SiegfriedGroup), SB-206553 and SB-242084 (SmithKline Beecham), SR-46615A (SanofiRecherche SA), SUN-9221 (Suntory Ltd) tropoxin (Russian Academy MedicalScience) and YM-992 (Yamanouchi Pharmaceutical Co Ltd).
 49. A productaccording to claim 25 in which the 5-HT2C receptor antagonist isselected from the group consisting of Ro-60-0759, RS-102221,SDZ-SER-082, ICI-169369, deramciclane, N-desmethyl-deramciclane,amesergide, sergolexole, CGS-18102A and LU-26042.
 50. A productaccording to claim 25 in which the 5-HT2C receptor antagonist isselected from the group consisting of deramciclane,N-desmethyl-deramciclane, amesergide, sergolexole, CGS-18102A andLU-26042.
 51. A product according to claim 25 in which the 5-HT2Creceptor antagonist is selected from the group consisting of ritanserin,clozapine, fluperlapine, loxapine, ORG-5222, pipamperone, sertindole,olanzapine, zotepine and ziprasidone, with the proviso that when thesuicidality is in a schizophrenic patient, the 5-HT2C receptorantagonist is other than clozapine.